Macrocyclic compound for inhibiting EGFR and inducing EGFR degradation, preparation method therefor and pharmaceutical use thereof

Abstract

The present disclosure relates to a macrocyclic compound for inhibiting EGFR and inducing EGFR degradation, a preparation method therefor and the pharmaceutical use thereof. Specifically, the present disclosure relates to a macrocyclic compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a therapeutic agent, particularly the use thereof as an EGFR inhibitor and / or degrader, and the use thereof in the preparation of a drug for treating and / or preventing EGFR-mediated or EGFR-dependent diseases or conditions.

Description

Macrocyclic compounds that inhibit and induce EGFR degradation, their preparation methods, and their pharmaceutical applications. Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a macrocyclic compound of general formula (I), a method for its preparation, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, particularly as an EGFR inhibitor and / or degrader, and in the preparation of medicaments for the treatment and / or prevention of EGFR-mediated or dependent diseases or conditions. Background Technology

[0002] Lung cancer is one of the most common malignant tumors. Statistics show that in 2018, lung cancer was the cancer with the highest incidence rate globally, with 2.094 million new cases. In China, the number of new lung cancer cases in 2018 was 868,000, with an incidence rate of 0.062%, accounting for 41.4% of the global total. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) belongs to the cell surface receptor family with tyrosine kinase activity. EGFR mutation is the most common driver gene in NSCLC; approximately 40% of Chinese NSCLC patients have EGFR mutations, while 11-16% of patients in Western countries have EGFR mutations. Approximately 90% of EGFR mutations are deletions of exon 19 (Del19 mutation) and L858R point mutations in exon 21.

[0003] Several small molecule EGFR inhibitors have been approved for marketing and successfully applied to the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations, becoming one of the main treatment methods for patients with advanced NSCLC. First-generation EGFR tyrosine kinase inhibitors, represented by gefitinib and erlotinib, are reversibly binding targeted drugs that inhibit EGFR kinase activation by competitively binding to the EGFR kinase domain with ATP. However, most patients develop resistance after 10-12 months of treatment, with approximately 50% of patients developing resistance due to a secondary T790M mutation. Second-generation EGFR tyrosine kinase inhibitors, represented by afatinib, are irreversibly targeted drugs, but they cannot address the T790M mutation resistance issue, and their lack of selectivity for wild-type EGFR results in significant toxicity. The advent of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, overcame drug resistance caused by EGFR T790M gene mutations. It also showed strong inhibition of wild-type EGFR with good selectivity, achieving great success in clinical practice. However, new drug resistance can develop after 9-14 months of use. Studies have revealed that 6-26% of patients developed C797X or other EGFR-dependent gene mutations.

[0004] Currently, there is a lack of effective EGFR inhibitors on the market that target the EGFR C797S gene mutation as a single treatment. Therefore, it is necessary to develop new treatment methods for non-small cell lung cancer (NSCLC). Unlike EGFR inhibitors, PROTAC technology can degrade EGFR, which can more effectively inhibit the EGFR signaling pathway and has the potential to become a promising treatment method for NSCLC. Published patent applications for EGFR protein-targeting degradation agents include WO2024099395A1 and WO2024246838A1. Summary of the Invention

[0005] The purpose of this disclosure is to provide a compound of general formula (I), or a pharmaceutically acceptable salt thereof:

[0006] in:

[0007] Ring C is selected from heterocyclic, aryl, and heteroaryl groups; ring D is aryl or heteroaryl.

[0008] Ring A is selected from * The key is connected to W; Key and L 6 connect;

[0009] X, Y, and Z may be the same or different, and each is independently selected from bond, O, and S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0010] W is selected from bond, O, and S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0011] V is N or CR 0 ;

[0012] t1 and t2 are each independently 0, 1, 2 or 3;

[0013] a1 and a2 are each independently 0, 1, 2, 3, 4 or 5;

[0014] A 1 For N or CRA1 A 2 For N or CR A2 ;

[0015] R A1 R A2 and R 0 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl and cycloalkylalkyl;

[0016] X 1 X 2 and X 3 Whether they are the same or different, and each is independently N or CR X ;

[0017] X 4 and X 5 Whether they are the same or different, and each is independently N or CR 3 ;

[0018] R 2 R 3 R 5 and R X The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, deuteralkyl, deuteroxy, hydroxyl, alkenyl, alkynyl, cyano, NR 11 R 12 C(O)NR 11 R 12 alkylene NR 11 R 12 alkylene C(O)NR 11 R 12 OR 14 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v OR 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R 01 Replaced;

[0019] Or two Rs 3Together with the carbon atom attached thereto, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups; each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. 01 Replaced;

[0020] J 1 Selected from bond, O, S(O) v NR J C(O), C(O)NR J NR J C(O), (CR) c R d ) y cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently and optionally composed of one or more R groups. 02 Replaced;

[0021] J 2 J 3 J 4 J 5 and J 6 Same or different, and each is independently selected from the key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently optionally composed of one or more R groups. 6 Replaced;

[0022] L 1 L 2 L 3 L 4 L 5 and L 6 They may be the same or different, and each is independently selected from the bond, O, and S(O). v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L ), alkenyl, alkyneyl, cycloalkyl, heterocyclic, (CR) e R f ) u -Heterocyclic group, heterocyclic group-(CR) e R f ) u 、(CR e R f ) u -heterocyclic-(CR) e R f ) u aryl and heteroaryl; each of the alkenyl, alkyneyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally composed of one or more R 7 Replaced;

[0023] Each R a R b R c R d R e and R f The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected by one or more R 03 Replaced; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is optionally independently bound by one or more R... 03 Replaced;

[0024] R 4 R m R 11 R 12 R 13 R 14 R J and R L The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced;

[0025] Each R 6 R 7 R 8 R 01 R 02 and R 03 The same or different, and each independently selected from deuterium, oxo group, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 21 R 22 C(O)NR 21 R 22 alkylene NR 21 R 22 alkylene C(O)NR 21 R 22 NR 23 C(O)R 24 C(O)R 24 C(O)OR 24 S(O) v R 24 S(O) v OR 24 OR 24 S(O) v NR 21 R 22 =CR 15 R 16 =NR 23 , cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl;

[0026] R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, and heterocyclic groups;

[0027] Each R 21 R 22 R 23 and R 24 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0028] x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6;

[0029] u can be 0, 1, 2, 3, 4, 5, or 6;

[0030] a can be 0, 1, 2, 3, 4, 5, or 6; t can be 0, 1, 2, 3, 4, 5, or 6.

[0031] r is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

[0032] v can be 0, 1, or 2.

[0033] The purpose of this disclosure is to provide a compound of general formula (I), or a pharmaceutically acceptable salt thereof:

[0034] in:

[0035] Ring A is selected from * The key is connected to W; Key and L 6 connect;

[0036] X, Y, and Z may be the same or different, and each is independently selected from bond, O, and S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0037] W is selected from bond, O, and S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0038] V is N or CR 0 ;

[0039] t1 and t2 are each independently 0, 1, 2 or 3;

[0040] a1 and a2 are each independently 0, 1, 2, 3, 4 or 5;

[0041] A 1 For N or CR A1 A 2 For N or CR A2 ;

[0042] R A1 R A2 and R 0They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl and cycloalkylalkyl;

[0043] Ring C is selected from heterocyclic, aryl, and heteroaryl groups; ring D is aryl or heteroaryl.

[0044] X 1 X 2 and X 3 Whether they are the same or different, and each is independently N or CR X ;

[0045] X 4 and X 5 Whether they are the same or different, and each is independently N or CR 3 ;

[0046] R 2 R 3 R 5 and R X The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl, alkenyl, alkynyl, cyano, NR 11 R 12 C(O)NR 11 R 12 alkylene NR 11 R 12 alkylene C(O)NR 11 R 12 OR 14 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v OR 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R 01 Replaced;

[0047] Or two Rs 3 Together with the carbon atom attached thereto, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups; each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. 01 Replaced;

[0048] J 1 Selected from bond, O, S(O) v NR J C(O), C(O)NR J NR J C(O), (CR) c R d ) y cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently and optionally composed of one or more R groups. 02 Replaced;

[0049] J 2 J 3 J 4 J 5 and J 6 Same or different, and each is independently selected from the key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently optionally composed of one or more R groups. 6 Replaced;

[0050] L 1 L 2 L 3 L 4 L 5 and L 6 They may be the same or different, and each is independently selected from the bond, O, and S(O). v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR eR f ) u N(R L ), alkenyl, alkyneyl, cycloalkyl, heterocyclic, (CR) e R f ) u -Heterocyclic group, heterocyclic group-(CR) e R f ) u 、(CR e R f ) u -heterocyclic-(CR) e R f ) u aryl and heteroaryl; each of the alkenyl, alkyneyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally composed of one or more R 7 Replaced;

[0051] Each R a R b R c R d R e and R f The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is optionally independently bound by one or more R... 03 Replaced;

[0052] R 4 R m R 11 R 12 R 13 R 14 R J and R L The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced;

[0053] Each R 6 R 7 R 8 R 01 R 02and R 03 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 21 R 22 C(O)NR 21 R 22 alkylene NR 21 R 22 alkylene C(O)NR 21 R 22 NR 23 C(O)R 24 C(O)R 24 C(O)OR 24 S(O) v R 24 S(O) v OR 24 OR 24 S(O) v NR 21 R 22 =CR 15 R 16 =NR 23 , cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl;

[0054] R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, and heterocyclic groups;

[0055] Each R 21 R 22 R 23 and R 24 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0056] x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6;

[0057] u can be 0, 1, 2, 3, 4, 5, or 6;

[0058] a can be 0, 1, 2, 3, 4, 5, or 6; t can be 0, 1, 2, 3, 4, 5, or 6.

[0059] r is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

[0060] v can be 0, 1, or 2.

[0061] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring C is phenyl or a 5- or 6-membered heteroaryl; in some embodiments, the ring C is a 5-membered heteroaryl; in some embodiments, the ring C is a pyrazolyl.

[0062] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring D is phenyl or a 5- or 6-membered heteroaryl group; in some embodiments, ring D is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0063] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof:

[0064] in:

[0065] R 2 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl, alkenyl, alkynyl, cyano, NR 11 R 12 C(O)NR 11 R 12 alkylene NR 11 R 12 alkylene C(O)NR 11 R 12 OR 14 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v OR 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R 01 Replaced;

[0066] R 1 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, deuterated alkyl groups, deuterated alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups;

[0067] s is 0, 1, 2, or 3; t is 0, 1, 2, or 3;

[0068] Rings A, W, V, L 1 To L 6 J 1 To J 6 R 3 R 4 R 5 R 8 ,r,R 11 R 12 R 13 R 14 R 01 And v is as defined in general formula (I).

[0069] In some embodiments of this disclosure, J 1 Selected from bond, O and NR J In some implementation schemes, J 1 For key or O; in some implementations, J 1 It is O.

[0070] In some embodiments of this disclosure, J 2 For key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 2 For key or (CR) c R d ) y In some implementation schemes, J 2 For bond or (CH2) y In some implementation schemes, J 2 As the key; where R c R d y, v, R J and R 6 As defined in general formula (I).

[0071] In some embodiments of this disclosure, J 3 For key, (CR c R d ) y1 O, S(O) v NR J C(O), C(O)NR JNR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 3 For key or (CR) c R d ) y1 In some implementation schemes, J 3 For (CR) c R d ) y1 In some implementation schemes, J 3 (CH2) y1 Where y1 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, J 3 CH2; where R c R d v, R J and R 6 As defined in general formula (I).

[0072] In some embodiments of this disclosure, J 4 For key, (CR c R d ) y1 O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; where R c R d y1, v, R J and R 6 As defined in general formula (I); in some implementations, J 4 It is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, J 4 It is a 3- to 12-membered cycloalkyl group; in some embodiments, J 4 It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; in some embodiments, J 4 The alkyl group is a 3- to 6-membered cycloalkyl group, each of which is optionally independently coupled with one or more R groups. 6 Replaced; R 6 As defined in general formula (I); in some implementations, J 4 Selected from cyclopropyl, cyclobutyl, cyclopentyl, pyrrolyl, and tetrahydrofuranyl; in some embodiments, J4 Selected from cyclopropyl, cyclobutyl, and cyclopentyl.

[0073] In some embodiments of this disclosure, J 5 For key, (CR c R d ) y2 O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 5 For key, (CR c R d ) y1 O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 5 For key or (CR) c R d ) y2 In some implementation schemes, J 5 For (CR) c R d ) y2 In some implementation schemes, J 5 (CH2) y2 Where y2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, J 5 CH2; where R c R d v, R J and R 6 As defined in general formula (I).

[0074] In some embodiments of this disclosure, J 6 For key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR JC(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 6 For key or (CR) c R d ) y In some implementation schemes, J 6 For bond or (CH2) y In some implementation schemes, J 6 As the key; where R c R d y, v, R J and R 6 As defined in general formula (I).

[0075] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0076] Wherein, ring B is a cycloalkyl or heterocyclic group;

[0077] B 1 B 2 and B 3 Whether they are the same or different, and each is independently N or CR 7a ;R 7a For hydrogen atoms or R 7 ;

[0078] R 1 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, deuterated alkyl groups, deuterated alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups;

[0079] s is 0, 1, 2, or 3; t is 0, 1, 2, or 3; s1 is 0 or 1;

[0080] b1 and b2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently;

[0081] m, p, q, y1 and y2 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6;

[0082] y3 and y4 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6;

[0083] Rings A, V, L 3 L 5 、u、J 1 R 2To R 8 And r are as defined in general formula (I).

[0084] In some implementation schemes, R 1 It is selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0085] In some embodiments of this disclosure, for R 2 To R 5 J 1 To J 6 X 4 X 5 a and t are as defined in general formula (I).

[0086] In some embodiments of this disclosure, for R 1 To R 5 J 1 To J 6 , s and t are as defined in general formula (I).

[0087] In some embodiments of this disclosure, for R 1 To R 6 , m, J 1 y1 to y4, s and t are as defined in general formula (II).

[0088] In some embodiments of this disclosure, the general formula (IIIN) is shown as follows: for R 1 To R 6 , m, J 1 E 1 E 2 y1, y2, s and t are defined as in general formula (IIIN).

[0089] In some embodiments of this disclosure, ring A is selected from... z is 0, 1, 2, or 3; X, Y, t1, t2, a1, a2, A 1 A 2 and R X As defined in general formula (I); in some implementations, ring A is selected from... z is 0, 1, 2, or 3; X, t1, t2, a1, a2, and R XAs defined in general formula (I); in some implementations, ring A is selected from... z is 0, 1, 2, or 3; each group is as defined in general formula (I); in some embodiments, ring A is selected from... z is 0, 1, 2, or 3; X, t1, t2, a1, a2, A 2 and R X As defined in general formula (I);

[0090] In some implementations, ring A is selected from... z is 0, 1, 2, or 3; X, Y, t1, t2, a1, a2, A 1 A 2 and R X As defined in general formula (I);

[0091] In some implementations, ring A is selected from... z is 0, 1, 2, or 3; X, t1, t2, a1, a2, A 2 and R X As defined in general formula (I);

[0092] In some implementations, ring A is selected from... In some implementations, ring A is selected from... The aforementioned ring can be arbitrarily selected by R. 8 Replace in a replaceable position; R 8 As defined above;

[0093] In some implementations, ring A is selected from... The aforementioned ring can be arbitrarily selected by R. 8 Replace in a replaceable position; in some embodiments, ring A is selected from The aforementioned ring can be arbitrarily selected by R. 8 Replace in a replaceable position; in some embodiments, ring A is selected from The aforementioned ring can be arbitrarily selected by R. 8 Replace in a replaceable position; R 8 As defined above.

[0094] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (IM), or pharmaceutically acceptable salts thereof, are compounds represented by general formulas (IIIN), (IVN), and (VN), or pharmaceutically acceptable salts thereof:

[0095] Among them, E 1 Selected from key, (CR) g R h ) y3 、(CR g R h ) y5 O(CR g R h ) y6 and (CR) g R h ) y5 NR m (CR g R h ) y6 ;

[0096] E 2 Selected from (CR) g R h ) y4 、(CR g R h ) y7 O(CR g R h ) y8 and (CR) g R h ) y7 NR m (CR g R h ) y8 ;

[0097] R g For hydrogen atoms or R 6 ;R h For hydrogen atoms or R 6 m can be 0, 1, or 2;

[0098] y5 and y6 are each independently 0, 1 or 2; y7 and y8 are each independently 0, 1 or 2.

[0099] W, V, X 1 X 2 X 3 ,X,Y,t1,t2,a1,a2,A 1 A 2 R 8 ,r,L 5 B 1 B 2B 3 Ring B, b1, b2, s1, u, J 1 y1 to y4, R m R 1 To R 7 p, q, s and t are as defined in general formula (II).

[0100] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (IM), or pharmaceutically acceptable salts thereof, are compounds represented by general formulas (IIIM), (IVM), and (VM), or pharmaceutically acceptable salts thereof:

[0101] Among them, W, V, X 1 X 2 X 3 ,X,Y,t1,t2,a1,a2,A 1 A 2 R 8 ,r,L 5 B 1 B 2 B 3 Ring B, b1, b2, s1, u, J 1 y1 to y4, m, R 1 To R 7 p, q, s and t are as defined in general formula (II).

[0102] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IM), and (II), or pharmaceutically acceptable salts thereof, are compounds represented by general formulas (III), (IV), or (V), or pharmaceutically acceptable salts thereof:

[0103] in,

[0104] z can be 0, 1, 2, or 3;

[0105] X, Y, V, t1, t2, a1, a2, A 1 A 2 R X L 5 B 1 B 2 B 3 Ring B, u, J 1 R 1 To R 7 , s, t, y1 to y4, m, b1, b2, s1, p and q are as defined in general formula (I).

[0106] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IM), and (VN), or pharmaceutically acceptable salts thereof, are compounds represented by general formulas (VI), (VII-1), (VII-2), (VII-3), (VII-4), and (VIII), or pharmaceutically acceptable salts thereof:

[0107] Among them, E 1 E 2 R 1 R 2 R 3 , u, ring B, B 3 R 7 , q, L 5 A 2 R 8 r, t1, t2, X 3 R X B 1 and B 2 As defined in general formulas (I), (II) or (VN).

[0108] In some embodiments of this disclosure, Y is selected from bond, O, S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O); R a R b v, x and R m As defined in general formula (I); in some embodiments, Y is selected from bond, O and CH2; in some embodiments, Y is bond or O; in some embodiments, Y is O.

[0109] In some embodiments of this disclosure, t1 is 0 or 1, and / or t2 is 0 or 1; in some embodiments, t1 is 0 or 1, and / or t2 is 1; in some embodiments, t1 is 0, and / or t2 is 1; in some embodiments, t1 is 0, and / or t2 is 0.

[0110] In some embodiments of this disclosure, t1 is 0, 1, or 2; in other embodiments, t1 is 0.

[0111] In some embodiments of this disclosure, t2 is 0, 1, or 2; in some embodiments, t2 is 2; and in some embodiments, t2 is 1.

[0112] In some embodiments of this disclosure, a1 is 0 or 1, and / or a2 is 0 or 1; in other embodiments, a1 is 1, and / or a2 is 1.

[0113] In some embodiments disclosed herein, A 1 For CH or N; in some implementations, A 1 Let N be the number of elements in the array.

[0114] In some embodiments disclosed herein, A 2 Selected from CH, N, CF and C-OH; in some embodiments, A 2 For CH or N; in some implementations, A 2 For N; in some implementations, A 2 For CH.

[0115] In some embodiments of this disclosure, X is selected from bond, O, S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O); R a R b v, x and R m As defined in general formula (I); in some embodiments, X is selected from bond, O, CH2 and CH2CH2; in some embodiments, X is selected from bond, O and CH2; in some embodiments, X is bond or O; in some embodiments, X is O.

[0116] In some embodiments of this disclosure, Z is selected from bond, O, S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O); R a R b v, x and R m As defined in general formula (I); in some implementations, Z is (CR a R b ) x In some implementations, Z is CH2.

[0117] In some embodiments of this disclosure, Y is O, and / or X is O, and / or Z is CH2.

[0118] In some embodiments of this disclosure, Y is 0, and / or X is 0.

[0119] In some embodiments of this disclosure, Y is a bond or O, and / or X is selected from bonds, O and CH2, and / or A. 1 For CH or N, and / or A 2 Selected from CH, N, CF and C-OH, and / or a1 is 0 or 1, and / or a2 is 0 or 1, and / or t1 is 0 or 1, and / or t2 is 0 or 1; in some embodiments, Y is O, and / or X is a bond or O, and / or A 1 For CH or N, and / or A 2 For CH or N, and / or a1 is 0 or 1, and / or a2 is 0 or 1, and / or t1 is 0 or 1, and / or t2 is 0 or 1; in some embodiments, Y is O, and / or A 1 For N, and / or A 2 It is CH or N, and / or a1 is 1, and / or a2 is 1, and / or t1 is 0, and / or t2 is 1.

[0120] In some embodiments disclosed herein, X 1 For N or CR X In some implementation schemes, X 1 For CR X R X As defined in general formula (I); in some implementations, X 1 Selected from N, CH, and CF; in some implementations, X 1 For CH or CF; in some implementations, X 1 For CH.

[0121] In some embodiments disclosed herein, X 2 For N or CR X In some implementation schemes, X 2 For CR X R X As defined in general formula (I); in some implementations, X 2 Selected from N, CH, and CF; in some implementations, X 2 For CH or CF; in some implementations, X 2 For CF.

[0122] In some embodiments disclosed herein, X 3 For N or CR X In some implementation schemes, X 3 For CR X R X As defined in general formula (I); in some implementations, X 3Selected from N, CH, and CF; in some implementations, X 3 For CH or CF; in some implementations, X 3 For CF.

[0123] In some embodiments disclosed herein, X 1 Selected from N, CH and CF, and / or X 2 Selected from N, CH and CF, and / or X 3 Selected from N, CH, and CF; in some implementations, X 1 For CH, and / or X 2 For CF, and / or X 3 For CF; in some implementations, X 1 For CH, and / or X 2 For CH or CF, and / or X 3 Selected from N, CH, and CF; in some implementations, X 1 For CH, and / or X 2 For CF, and / or X 3 For CF.

[0124] In some embodiments disclosed herein, X 4 Selected from N, CH and CF.

[0125] In some embodiments disclosed herein, X 5 Selected from N, CH and CF.

[0126] In some embodiments of this disclosure, W is selected from bond, NH, NHC(O) and C(O)NH; in some embodiments, W is bond or NH; in some embodiments, W is bond.

[0127] In some embodiments of this disclosure, V is CH or N; in other embodiments, V is CH.

[0128] In some embodiments disclosed herein, E 1 Selected from (CH2) y3 (CH2) y5 O, O(CH2) y6 (CH2) y5 NR m and NR m (CH2) y6 ;R m y3, y5, and y6 are as defined in general formula (IIIN); in some implementations, E 1 Selected from (CH2) y3 O and NR m In some implementation schemes, E 1 Selected from CH2, O and NR mIn some implementation schemes, E 1 Selected from CH2, O, NH and N methyl; in some embodiments, E 1 It is CH2 or O; in some implementations, E 1 For CH2; in some implementations, E 1 It is O.

[0129] In some embodiments disclosed herein, E 2 Selected from (CH2) y4 (CH2) y7 O, O(CH2) y8 (CH2) y7 NR m and NR m (CH2) y8 ;R m y4, y7, and y8 are as defined in general formula (IIIN); in some implementations, E 2 Selected from (CH2) y4 CH2O, OCH2, CH2NR m and NR m CH2; In some implementations, E 2 Selected from CH2, CH2CH2, O and NR m In some implementation schemes, E 2 Selected from CH2, CH2CH2, O, CH2O, OCH2, CH2NR m and NR m CH2; R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, E 2 Selected from CH2, CH2CH2, O, CH2O, OCH2, CH2N methyl and methyl NCH2; in some embodiments, E 2 It is CH2 or CH2CH2; in some implementations, E 2 It is CH2CH2.

[0130] In some embodiments disclosed herein, E 1 Selected from (CH2) y3 (CH2) y5 O, O(CH2) y6 (CH2) y5 NR m and NR m (CH2) y6 ; and / or E 2 Selected from (CH2) y4 (CH2) y7 O, O(CH2) y8 (CH2)y7 NR m and NR m (CH2) y8 ;R m y3 to y8 are as defined in general formula (IIIN); in some implementations, E 1 Selected from CH2, O and NR m , and / or E 2 Selected from CH2, CH2CH2, CH2O, OCH2, CH2NR m and NR m CH2; R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, E 1 For CH2 or O, and / or E 2 It is CH2CH2.

[0131] In some embodiments disclosed herein, J 4 or Selected from In some of these implementation schemes,

[0132] In some embodiments disclosed herein, J 4 or Selected from In some implementation schemes,

[0133] These rings are optionally bounded by one or more R 6 What it replaced.

[0134] In some implementation schemes disclosed herein, Selected from In some implementation schemes, Selected from These rings are optionally bounded by one or more R 6 Replaced; in some implementations, these rings are optionally replaced by 1, 2, 3, 4, 5 or 6 Rs. 6 What it replaced.

[0135] In some implementation schemes disclosed herein, Selected from

[0136] In some embodiments disclosed herein, L 1 Selected from bond, O, S(O)v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 1 For bond or (CH2) u u is as defined in general formula (I); in some implementations, L 1Selected from bond, O, CH2, CH2CH2, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 1 For key.

[0137] In some embodiments disclosed herein, L 2 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, RL R 7 As defined in general formula (I); in some implementations, L 2 Selected from alkyl groups, 3- to 12-membered cycloalkyl groups, and 3- to 12-membered heterocyclic groups; in some embodiments, L 2 Selected from bonds, 5- or 6-membered cycloalkyl groups, and 5- or 6-membered heterocyclic groups; in some embodiments, L 2 For key or B 1 B 2 b1, b2 are as defined in general formula (II); in some implementations, L 2 For a bond or piperidinyl group; in some embodiments, L 2 For key or

[0138] In some embodiments disclosed herein, L 3 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) eR f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 3 For bond or (CH2) u u is as defined in general formula (I); in some implementations, L 3 Selected from bond, O, CH2, CH2CH2, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 3 For key.

[0139] In some embodiments disclosed herein, L 4 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u-3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 4 It is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, L 4 It is a 3- to 10-membered heterocyclic group; in some implementations, L 4 It is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; in some embodiments, L 4 for B 3 For CH or N, B 4 b3 is CH or N; b4 is 0, 1, or 2; b4 is 0, 1, or 2; in some implementations, L 4 It is piperidinyl or piperazine; in some embodiments, L 4 for

[0140] In some embodiments of this disclosure, ring B is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; ring B is a 3- to 10-membered heterocyclic group; in some embodiments, ring B is... B 3 For CH or N, B 4 b3 is CH or N; b4 is 0, 1, or 2; in some embodiments, ring B is piperidinyl or piperazineyl; in some embodiments, ring B is... In some implementation schemes, ring B is

[0141] In some embodiments disclosed herein, L 5 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR eR f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u2 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); u2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, L 5 For bond or (CH2) u2 u2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, L 5 (CH2) u2 u2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, L 5Selected from bond, O, CH2, CH2CH2, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 5 For CH2; in some implementations, L 5 For key.

[0142] In some embodiments disclosed herein, L 6 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; Re R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 6 For bond or (CH2) u u is as defined in general formula (I); in some implementations, L 6 Selected from bond, O, CH2, CH2CH2, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 6 For key.

[0143] In some embodiments disclosed herein, L 1 L 2 L 3 L 4 L 5 or L 6 Same or different, and each independently selected from bonds, CH2, CH2CH2, O, C(O), NH, NHC(O), C(O)NH, (In some embodiments, these rings are optionally selected from oxo groups, halogens, C...) 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 (One or more of the hydroxyalkyl groups are substituted).

[0144] In some embodiments of this disclosure, -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、 Selected from

[0145] In some embodiments disclosed herein, B 1 For N or CH, and / or B 2 For N or CH; in some implementations, B 1 For CH or N, and / or B 2 For N; in some implementations, B 1 For N, and / or B 2 For CH; in some implementations, B 1 For N, and / or B 2 Let N be the number of elements in the array.

[0146] In some embodiments disclosed herein, B 3 For N, and / or B 4 Let N be the number of elements in the array.

[0147] In some embodiments of this disclosure, b1 is 0 or 1, and / or b2 is 0 or 1; in other embodiments, b1 is 1, and / or b2 is 1.

[0148] In some embodiments of this disclosure, b3 is 1 or 2, and / or b4 is 1 or 2; in some embodiments, b3 is 1, and / or b4 is 1.

[0149] In some embodiments of this disclosure, s1 is 0; in other embodiments, s1 is 1.

[0150] In some embodiments disclosed herein, B 1 For CH or N, and / or B 2 For CH or N, and / or B 3 The form is CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1, and / or ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; in some embodiments, B 1 For CH or N, and / or B 2 For CH or N, and / or B 3 It is CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1, and / or ring B is piperidinyl or piperazine.

[0151] In some embodiments of this disclosure, s1 is 1, and / or u is 0 or 1, and / or L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; in some implementations, u is 0 or 1, and / or L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; in some implementations, u is 0, and / or L 5 For a bond or CH2; in some implementations, u is 0, and / or L 5 For key.

[0152] In some embodiments of this disclosure, u is 0, 1, or 2; in other embodiments, u is 0.

[0153] In some embodiments of this disclosure, u2 is 0, 1, or 2; in other embodiments, u2 is 0 or 1.

[0154] In some embodiments disclosed herein, J 1For a key or 0, and / or y1 is 0, 1, 2 or 3, and / or y2 is 0, 1 or 2, and / or y3 is 0, 1 or 2, and / or y4 is 1 or 2; in some implementations, J 1 For y1, y2 is 0, y3 is 0, 1, or 2, and / or y4 is 1 or 2; in some implementations, J 1 If y1 is 0, and / or y2 is 1, and / or y3 is 1, and / or y4 is 1 or 2.

[0155] In some embodiments of this disclosure, y1 is 0, 1, 2 or 3, and / or y2 is 0, 1, 2 or 3; in some embodiments, y1 is 1, and / or y2 is 1.

[0156] In some embodiments of this disclosure, y3 is 0, 1, or 2, and / or y4 is 1 or 2; in other embodiments, y3 is 1, and / or y4 is 1.

[0157] In some implementations, y4 is 2.

[0158] In some embodiments of this disclosure, y5 is 0 or 1, and / or y6 is 0 or 1; in other embodiments, y5 is 0, and / or y6 is 0.

[0159] In some embodiments of this disclosure, y7 is 0 or 1, and / or y8 is 0 or 1; in some embodiments, y7 is 0, and / or y8 is 1, or y7 is 1, and / or y8 is 0.

[0160] In some embodiments disclosed herein, each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R X It is a hydrogen atom or a halogen; in some implementations, R X For hydrogen atoms or F; in some implementations, R X For halogen; in some implementations, R X It is F.

[0161] In some embodiments of this disclosure, z is 0, 1, or 2; in some embodiments, z is 2.

[0162] In some embodiments disclosed herein, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups; in some embodiments, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 1 C 1-6 Alkyl; in some embodiments, R 1 For methyl; in some embodiments, R 1 Selected from methyl, CD3, cyclopropyl and oxecyclobutyl.

[0163] In some embodiments disclosed herein, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyl alkyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 2 It is a hydrogen atom or a methyl group; in some embodiments, R 2 For hydrogen atoms; in some implementations, R 2 C 1-6 Alkyl; in some embodiments, R 2 It is a methyl group.

[0164] In some embodiments disclosed herein, each R3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 It is a methyl group.

[0165] In some embodiments of this disclosure, s is 0, 1, or 2; in other embodiments, s is 1.

[0166] In some embodiments disclosed herein, R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 4 It is a hydrogen atom.

[0167] In some embodiments disclosed herein, each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0168] In some embodiments of this disclosure, t is 0, 1, or 2; in other embodiments, t is 0.

[0169] In some embodiments disclosed herein, R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Deuterated alkyl, C 3-6 cycloalkyl and C 3-6 Heterocyclic groups, and / or R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups, and / or R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups, and / or R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl, and / or R 5 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups, and / or each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1 C 1-6 Alkyl, and / or R 2 For hydrogen atoms, and / or R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms, and / or R 5 For hydrogen atoms, and / or each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3 to 6-membered cycloalkyl groups.

[0170] In some embodiments disclosed herein, each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0171] In some embodiments of this disclosure, m is 0, 1, or 2; in other embodiments, m is 0.

[0172] In some embodiments disclosed herein, each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0173] In some embodiments of this disclosure, p is 0, 1, or 2; in other embodiments, p is 0.

[0174] In some embodiments of this disclosure, q is 0, 1, or 2; in other embodiments, q is 0.

[0175] In some embodiments disclosed herein, each R 8 They may be the same or different, and each is independently selected from deuterium atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0176] In some embodiments of this disclosure, r is 0, 1, 2, 3 or 4; in some embodiments, r is 0, 1 or 2; in some embodiments, r is 0.

[0177] In some embodiments of this disclosure, v is 0; in other embodiments, v is 2.

[0178] In some embodiments disclosed herein, each R a and R b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R a and R b It is a hydrogen atom.

[0179] In some embodiments of this disclosure, x is 0, 1, 2, 3 or 4; in other embodiments, x is 0, 1 or 2.

[0180] In some embodiments disclosed herein, R m Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R m It can be a hydrogen atom or a methyl group.

[0181] In some embodiments disclosed herein, R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 0 It is a hydrogen atom.

[0182] In some embodiments disclosed herein, R A1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R A1 It is a hydrogen atom.

[0183] In some embodiments disclosed herein, R A2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R A2 It is a hydrogen atom.

[0184] In some implementation schemes disclosed herein, for

[0185] In some implementation schemes disclosed herein, for

[0186] In some implementation schemes disclosed herein, or for In some implementation schemes, or for

[0187] In some embodiments disclosed herein, R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a methyl group.

[0188] In some embodiments disclosed herein, R 13 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0189] In some embodiments disclosed herein, R 14 Selected from hydrogen atoms, C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups.

[0190] In some embodiments disclosed herein, R J It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0191] In some embodiments disclosed herein, each R c and R d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R c and R d It is a hydrogen atom.

[0192] In some embodiments of this disclosure, y is 0, 1, 2, 3 or 4; in other embodiments, y is 0, 1 or 2.

[0193] In some embodiments disclosed herein, R L It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0194] In some embodiments disclosed herein, each R e and R f They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R e and R f It is a hydrogen atom.

[0195] In some embodiments disclosed herein, each R 01 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3 to 6-membered cycloalkyl groups.

[0196] In some embodiments disclosed herein, each R 02 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3 to 6-membered cycloalkyl groups.

[0197] In some embodiments disclosed herein, each R 03 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3 to 6-membered cycloalkyl groups.

[0198] In some embodiments of this disclosure, the compounds represented by the general formulas (IIIM), (IVM), (VM), (IIIN), (IVN), or (VN), or their pharmaceutically acceptable salts, wherein W is a bond or NH; V is CH or N; Y is a bond or O; X is selected from bonds, O, and CH2; A 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, and t2 is 0, 1, or 2; X 1 For N or CR X ;X 2 For N or CR X ;X 3 For N or CR X Each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; r is 0, 1 or 2; L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; B 1 For CH or N, B 2 For CH or N, B 3 For CH or N, b1 is 0 or 1, b2 is 0 or 1, ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, or 2; q is 0, 1, or 2; s1 is 0 or 1; u is 0 or 1; J 1 For y1, y2, y3, y4, and y4, y1 is 0, 1, or 2; for y2, y3 is 0, 1, or 2; for y4, y4 is 1 or 2. 1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6Haloalkyl; s is 0, 1, or 2; t is 0, 1, or 2; each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2.

[0199] In some embodiments of this disclosure, the compounds represented by the general formulas (IIIM), (IVM), (VM), (IIIN), (IVN), or (VN), or their pharmaceutically acceptable salts, wherein, for W represents a bond or NH; Y represents a bond or O; X is selected from bonds, O, and CH2; A 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, and t2 is 0, 1, or 2; X 1 Selected from N, CH and CF; X 2 Selected from N, CH and CF; X 3 Selected from N, CH and CF; r is 0; L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; B 1 For CH or N, B 2 For CH or N, B 3 For CH or N, b1 is 0 or 1, b2 is 0 or 1, ring B is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; p is 0; q is 0; s1 is 0 or 1; u is 0 or 1; J 1 For y1, y2, y3, y4, and y4, y1 is 0, 1, or 2; for y2, y3 is 0, 1, or 2; for y4, y4 is 1 or 2. 1 C 1-6 Alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 4 For hydrogen atoms; s is 1; t is 0; m is 0.

[0200] In some embodiments of this disclosure, the compound represented by general formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein Y is O, X is a bond or O, and A 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0 or 1; V is CH or N; each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms.1-6 Alkyl and C 1-6 Haloalkyl; z is 0, 1, or 2; u is 0 or 1, L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; B 1 For CH or N, B 2 For CH or N, B 3 For CH or N, b1 is 0 or 1, b2 is 0 or 1, ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, or 2; q is 0, 1, or 2; s1 is 0 or 1; J 1 For y1, y2, y3, y4, and y4, y1 is 0, 1, or 2; for y2, y3 is 0, 1, or 2; for y4, y4 is 1 or 2. 1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; s is 0, 1, or 2; t is 0, 1, or 2; each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2.

[0201] In some embodiments of this disclosure, the compound represented by general formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein, for Y represents O, X represents a bond or O, and A represents... 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0 or 1; each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; z is 0, 1, or 2; u is 0 or 1, L 5 For bond or (CH2)u2 u2 is 0, 1, or 2; B 1 For CH or N, B 2 For CH or N, B 3 For CH or N, b1 is 0 or 1, b2 is 0 or 1, ring B is piperidinyl or piperazine; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, or 2; q is 0, 1, or 2; s1 is 0 or 1; J 1 For y1, y2, y3, y4, and y4, y1 is 0, 1, or 2; for y2, y3 is 0, 1, or 2; for y4, y4 is 1 or 2. 1 C 1-6 Alkyl; R 2 For hydrogen atoms; each R 3 The same or different, and each independently is C. 1-6 Alkyl; R 4 For hydrogen atoms; s is 1; t is 0; m is 0.

[0202] In some embodiments of this disclosure, the compound represented by the general formula (IIIN) or (VN) or its pharmaceutically acceptable salt, wherein W is a bond or NH; V is CH or N; Y is a bond or O; X is selected from bonds, O and CH2; A 1 For CH or N, A 2 For N or CR A2 ;R A2 Selected from hydrogen atom, halogen, hydroxyl group, C 1-6 Alkyl and C 1-6 Haloalkyl; a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0, 1 or 2; X 1 For N or CR X ;X 2 For N or CR X ;X 3 For N or CR X Each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; r is 0, 1 or 2; L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; B 1 For CH or N, B 2 For CH or N, B 3For CH or N, b1 is 0 or 1, b2 is 0 or 1, ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, and C. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, or 2; q is 0, 1, or 2; s1 is 0 or 1; u is 0 or 1; J 1 For a key or O, y1 is 0, 1, 2, or 3, y2 is 0, 1, or 2, E 1 Selected from (CH2) y3 O and NR m E 2 Selected from (CH2) y4 (CH2) y7 O, O(CH2) y8 (CH2) y7 NR m and NR m (CH2) y8 ;R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; y3 is 0, 1, or 2; y4 is 1 or 2; y7 is 0 or 1; y8 is 0 or 1; R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; s is 0, 1, or 2; t is 0, 1, or 2; each R 6 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2.

[0203] In some embodiments of this disclosure, the compound represented by the general formula (IIIN) or its pharmaceutically acceptable salt, wherein W is a bond or NH; V is CH; Y is a bond or O, t1 is 0, t2 is 1; X is selected from bonds, O and CH2, A 1 For CH or N, A2 For N or CR A2 ;R A2 Selected from hydrogen atom, halogen, hydroxyl group, C 1-6 Alkyl and C 1-6 Haloalkyl; a1 is 1, a2 is 1, X 1 For CH; X 2 For N or CR X ;X 3 For N or CR X Each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; r is 0; L 5 For the key, s1 is 0; p is 0; B 3 For CH or N, ring B is a 3- to 10-membered heterocyclic group; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, and C. 1-6 Alkyl and C 1-6 Haloalkyl; q is 0, 1, or 2; u is 0; t is 0; J 1 Given 0, y1 is 1, y2 is 1, E 1 It is CH2 or O; E 2 It is CH2 or CH2CH2; m is 0; R 1 C 1-6 Alkyl; R 2 C 1-6 Alkyl; R 3 C 1-6 Alkyl; s is 1; R 4 It is a hydrogen atom.

[0204] In some embodiments of this disclosure, the compound represented by the general formula (VN) or its pharmaceutically acceptable salt, wherein W is a bond; V is CH; Y is O, t1 is 0, t2 is 1; A 1 For CH or N, A 2 For N or CR A2 ;R A2 Selected from hydrogen atom, halogen, hydroxyl group, C 1-6 Alkyl and C 1-6 Haloalkyl; a1 is 1, a2 is 1, X 1 For CH; X 2 For N or CR X ;X 3 For N or CR X Each R X They may be the same or different, and each is independently a hydrogen atom or a halogen; r is 0; L 5 For the key, s1 is 0, p is 0; B 3For CH or N, ring B is a 3- to 10-membered heterocyclic group; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, and C. 1-6 Alkyl and C 1-6 Haloalkyl; q is 0, 1, or 2; u is 0; t is 0; J 1 Given 0, y1 is 1, y2 is 1, E 1 It is CH2 or O; E 2 It is CH2 or CH2CH2; m is 0; R 1 C 1-6 Alkyl; R 2 C 1-6 Alkyl; R 3 C 1-6 Alkyl; s is 1; R 4 It is a hydrogen atom.

[0205] In some embodiments of this disclosure, the compounds represented by general formulas (VII-1), (VII-2), (VII-3), and (VII-4), or their pharmaceutically acceptable salts, wherein R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups; R 2 C 1-6 Alkyl; R 3 C 1-6 Alkyl; E 1 It is CH2 or O; E 2 Selected from CH2, CH2CH2, CH2O, OCH2, CH2NR m and NR m CH2; R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl group; u is 0; ring B is a 3- to 10-membered heterocyclic group; B 3 For CH or N; q is 0, 1 or 2; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; L 5 For key; r is 0; A 2 For N or CR A2 ;R A2 Selected from hydrogen atom, halogen, hydroxyl group, C 1-6 Alkyl and C1-6 Halogenated alkyl; X 3 For N or CR X Each R X They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0206] In some embodiments of this disclosure, the compound represented by general formula (VIII) or a pharmaceutically acceptable salt thereof, wherein E 1 It is CH2 or O; E 2 Selected from CH2, CH2CH2, CH2O, OCH2, CH2NR m and NR m CH2; R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; B 1 For CH or N; B 2 For CH or N; A 2 For N or CH; each R X They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0207] Table A lists typical compounds disclosed herein, including but not limited to:

[0208] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof:

[0209] Among them, rings B and B 1 B 2 B 3 L 3 ,u,b1,b2,s1,p,q,J 1 R 1 To R 7 , s, t, y1 to y4 and m are as defined by general formula (II).

[0210] Another aspect of this disclosure relates to compounds of the general formula (IIINA) or (IIINA-1) or salts thereof:

[0211] Among them, R W It can be a hydrogen atom or an amino protecting group; in some embodiments, the amino protecting group is Boc.

[0212] Ring B, B 1 B 2 ,u,b1,b2,s1,p,q,J 1 E 1 E 2 R 1 To R 7 , s, t, y1, y2 and m are as defined by general formula (IIIN).

[0213] Another aspect of this disclosure relates to compounds of general formula (IIIA) or (IVA) or salts thereof:

[0214] Among them, R W It can be a hydrogen atom or an amino protecting group; in some embodiments, the amino protecting group is Boc.

[0215] Ring B, B 1 B 2 ,u,b1,b2,s1,p,q,J 1 R 1 To R 7 , s, t, y1 to y4 and m are as defined by general formula (III).

[0216] Another aspect of this disclosure relates to compounds of general formulas (VMB), (VMB-1), (VMB-2), or salts thereof:

[0217] Each group is as defined in general formula (VM).

[0218] Another aspect of this disclosure relates to compounds of general formulas (IIIB), (IV-1B), (VB), (IV-2B), (IV-3B), (IVB), (V-1B), (V-2B), (V-3B), (V-4B), or salts thereof (in some embodiments, hydrochloride salts or trifluoroacetates):

[0219] Among them, R W It can be a hydrogen atom or an amino protecting group; in some embodiments, the amino protecting group is Boc.

[0220] X, Y, V, t1, t2, a1, a2, L 6 A1 R X z is as defined in general formulas (III), (IV) or (V).

[0221] Another aspect of this disclosure relates to compounds of general formulas (VC), (VD), (VE) or salts thereof:

[0222] Among them, R W It is a hydrogen atom or an amino protecting group; R 17 R is a leaving group; 18 It is a hydrogen atom or a halogen; R P It is a hydrogen atom or hydroxyl protecting group; in some embodiments, R W For hydrogen atoms or Cbz, R 17 It is a halogen; R 18 For halogen; in some implementations, R 17 For F; R 18 For Br; each group is as defined in general formula (V).

[0223] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (Vc), (Vd), and (Ve):

[0224] Each group is as defined in general formula (V).

[0225] Another aspect of this disclosure relates to compounds of general formulas (VF), (VG), (VH), or salts thereof:

[0226] Where R W1 R is a hydrogen atom or amino protecting group. W As a hydrogen atom or amino protecting group, in some embodiments, R W1 For Cbz or Boc, R W It is either Cbz or Boc; each group is as defined in general formula (V).

[0227] In some embodiments disclosed herein, R W x represents a hydrogen atom. In some embodiments of this disclosure, x is 1.

[0228] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IIIC), (IIID), (IIIE), and (IIIF):

[0229] Where Xa is a halogen, R Q Selected from halogens, OH, and alkoxy groups; in some embodiments, X is Br, R Q It is a methoxy group; other groups are as defined above.

[0230] Table B lists typical intermediate compounds or salts thereof disclosed herein, including but not limited to:

[0231] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (III), (IV) or (V) or pharmaceutically acceptable salts thereof, the method comprising:

[0232] The compound of general formula (IIIA) or a salt thereof undergoes a reductive amination reaction with the compound of general formula (IIIB-1) or a salt thereof (in some embodiments, a hydrochloride salt) to give B. 3 For CH, L 5 As key and A 2 Compounds of general formula (III) for N or their pharmaceutically usable salts,

[0233] A compound of general formula (IVA) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with a compound of general formula (IVB) or a salt thereof to give B. 3 For N and L 5 Compounds of general formula (IV) representing CH2 or their pharmaceutically acceptable salts,

[0234] The compound of general formula (IIIA) or its salt reacts with the compound of general formula (VB-1) or its salt (in some embodiments, a trifluoroacetate) via a reductive amination reaction to give B. 3 For CH, L 5 As key and A 2 N represents a compound of general formula (V) or a pharmaceutically acceptable salt thereof.

[0235] in,

[0236] X, Y, V, t1, t2, a1, a2, R X ,z,A 1 B 1 B 2 Ring B, s1, b1, b2, p, q, u, J 1 R 1 To R 7 , s, t, y1 to y4 and m are as defined in general formulas (III), (IV) or (V).

[0237] This disclosure relates to a method for preparing a compound of the above general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0238] The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (V-3B) or its salt to yield the compound represented by general formula (V) or its pharmaceutically usable salt.

[0239] Among them, B 3 For N, L 5 As the key, A 2 For CH;

[0240] Y, V, t1, t2, a1, a2, R X ,z,A 1 B 1 B 2 Ring B, s1, b1, b2, p, q, u, J 1 R 1 To R 7 , s, t, y1 to y4 and m are as defined in general formula (V).

[0241] This disclosure relates to a method for preparing a compound of the above general formula (VM) or a pharmaceutically acceptable salt thereof, the method comprising:

[0242] The compound of general formula (IIIA) or its salt reacts with the compound of general formula (VMB-3) or its salt (in some embodiments, a trifluoroacetate or hydrochloride salt) via a reductive amination reaction to yield B. 3 For CH, L 5 As key and A 2 Compounds of the general formula (VM) for N or their pharmaceutically acceptable salts,

[0243] The compound of general formula (VA) or its salt (in some embodiments, a trifluoroacetate or hydrochloride salt) undergoes a reductive amination reaction with the compound of general formula (VMB-2) or its salt to give B. 3 For N, L 5 As key and A 2 Compounds of the general formula (VM) CH or pharmaceutically acceptable salts thereof

[0244] Among them, W, V, X 1 X 2 X 3 Y, t1, t2, a1, a2, A 1 R 8 ,r,B 1 B 2 Ring B, b1, b2, s1, u, J1 y1 to y4, m, R 1 To R 7 p, q, s and t are defined as in the general formula (VM).

[0245] This disclosure relates to a method for preparing a compound of the above general formula (IIIN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0246] The compound of general formula (IIINA) or its salt reacts with the compound of general formula (IIIB-1) or its salt (in some embodiments, trifluoroacetate or hydrochloride) via a reductive amination reaction to give B. 3 For CH, L 5 As key and A 2 Compounds of the general formula (IIIN) for N or their pharmaceutically acceptable salts, or

[0247] The compound of general formula (IIINA-2) or its salt (in some embodiments, a trifluoroacetate or hydrochloride salt) undergoes a reductive amination reaction with the compound of general formula (IIIB-2) or its salt to give B. 3 For N, L 5 As key and A 2 Compounds of the general formula (IIIN) of CH or their pharmaceutically acceptable salts.

[0248] Among them, W, V, X 1 X 2 X 3 ,X,Y,t1,t2,a1,a2,R 8 ,r,B 1 B 2 Ring B, b1, b2, s1, u, J 1 E 1 E 2 y1, y2, m, R 1 To R 7 p, q, s and t are as defined in general formula (IIIN).

[0249] This disclosure relates to a method for preparing a compound of the above general formula (VN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0250] The compound of general formula (IIINA) or its salt reacts with the compound of general formula (VMB-3) or its salt (in some embodiments, trifluoroacetate or hydrochloride) via a reductive amination reaction to give B. 3 For CH, L 5 As key and A 2Compounds of the general formula (VN) for N or their pharmaceutically acceptable salts, or

[0251] The compound of general formula (IIINA-2) or its salt (in some embodiments, a trifluoroacetate or hydrochloride salt) undergoes a reductive amination reaction with the compound of general formula (VMB-2) or its salt to give B. 3 For N, L 5 As key and A 2 Compounds of the general formula (VN) of CH or pharmaceutically acceptable salts thereof, wherein,

[0252] W, V, X 1 X 2 X 3 Y, t1, t2, a1, a2, A 1 R 8 ,r,B 1 B 2 Ring B, b1, b2, s1, u, J 1 E 1 E 2 y1, y2, m, R 1 To R 7 p, q, s and t are defined as in general formula (VN).

[0253] In some embodiments, the reductive amination reaction described above may optionally occur under acidic or basic conditions; in some embodiments, the reductive amination reaction described above occurs under acidic conditions; in some embodiments, the reductive amination reaction occurs under basic conditions.

[0254] Reagents providing acidic conditions include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, acetic acid, glacial acetic acid, Ti(i-PrO)3 ​​and BF3·Et2O, TiCl4, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, titanium tetrachloride, Me3SiCl, and TMSOTf. In some embodiments, the reagent providing acidic conditions is an added acidic reagent, and / or an acid introduced from the acidic salt of the reactants; in some embodiments, the reagent providing acidic conditions is an acid introduced from the acidic salt of the reactants; in some embodiments, the reagent providing acidic conditions is an acid introduced from the hydrochloride salt of the reactants.

[0255] The reagents providing alkaline conditions in the above synthesis schemes include organic and inorganic bases. The organic bases include, but are not limited to, N,N'-dimethylethylenediamine, triethylamine, N,N-diisopropylethylamine (diisopropylethylamine), N,N-diisopropylethylenediamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; in some embodiments, N,N-diisopropylethylamine is used.

[0256] In the above synthesis scheme, the above-mentioned reductive amination reaction occurs in the presence of a reducing agent; in some embodiments, the reducing agent includes, but is not limited to, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium borohydride acetate, sodium cyanoborohydride, and sodium acetylborohydride; in some embodiments, it is sodium triacetoxyborohydride.

[0257] The reactions described above can be carried out in a solvent, including but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof.

[0258] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formulas (I) to (VIII) of this disclosure and shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0259] This disclosure further relates to the use of compounds of general formulas (I) to (VIII) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for regulating EGFR ubiquitination and degradation.

[0260] This disclosure further relates to the use of compounds of general formulas (I) to (VIII) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on EGFR.

[0261] This disclosure further relates to the use of compounds of general formulas (I) to (VIII) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for treating and / or preventing cancer; in some embodiments, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal carcinoma, bronchial neoplasms, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0262] This disclosure also relates to a method for regulating the ubiquitination and degradation of EGFR protein in a subject, comprising administering to a desired patient a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0263] This disclosure also relates to a method of inhibiting and / or degrading EGFR protein, comprising administering to a desired patient a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0264] This disclosure also relates to a method of treating and / or preventing EGFR-mediated or dependent diseases or conditions, comprising administering to a desired patient a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0265] This disclosure also relates to a method of treating and / or preventing cancer, comprising administering to a desired patient a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above; in some embodiments, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0266] This disclosure further relates to a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0267] This disclosure further relates to a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicament for regulating the ubiquitination and degradation of EGFR protein in a subject.

[0268] This disclosure further relates to a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which acts as an EGFR inhibitor and / or degrader.

[0269] This disclosure further relates to a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on EGFR.

[0270] This disclosure further relates to compounds of the above general formulas (I) to (VIII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for regulating EGFR protein ubiquitination and degradation in a subject.

[0271] This disclosure further relates to compounds of the above general formulas (I) to (VIII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for inhibiting and / or degrading EGFR protein.

[0272] This disclosure further relates to compounds of the above general formulas (I) to (VIII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on EGFR.

[0273] This disclosure further relates to a compound of the above general formulas (I) to (VIII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, for the treatment and / or prevention of cancer; in some embodiments, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0274] In some embodiments, the EGFR-mediated or dependent diseases or conditions described in this disclosure are cancers; in some embodiments, the diseases or conditions are selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0275] In some embodiments, the lung cancer is small cell lung cancer or non-small cell lung cancer; in some embodiments, the non-small cell lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, or large cell lung cancer; in some embodiments, the head and neck cancer is head and neck squamous cell carcinoma; in some embodiments, the esophageal cancer is esophageal squamous cell carcinoma; and in some embodiments, the glioblastoma is glioblastoma multiforme.

[0276] In some embodiments, the cancer described in this disclosure is an EGFR protein with an L858R mutation.

[0277] In some embodiments, the cancer described in this disclosure is an EGFR protein with a 19del mutation.

[0278] In some embodiments, the cancer described in this disclosure is an EGFR protein with a T790M mutation.

[0279] In some embodiments, the cancer described in this disclosure is an EGFR protein with a C797X mutation.

[0280] In some embodiments, the cancer described in this disclosure is an EGFR protein with L858R and T790M mutations. In some embodiments, the cancer is an EGFR protein with 19del and T790M mutations. In some embodiments, the cancer is an EGFR protein with L858R and C797X mutations. In some embodiments, the cancer is an EGFR protein with 19del and C797X mutations. In some embodiments, the cancer is an EGFR protein with T790M and C797X mutations.

[0281] In some embodiments, the cancer is an EGFR protein with mutations L858R, T790M, and C797X. In some embodiments, the cancer is an EGFR protein with mutations 19del, T790M, and C797X. In some embodiments, the C797X mutation is a C797S mutation; where X represents any amino acid including S.

[0282] In this disclosure, formulas (I) to (VIII) include formulas (I), (IM), (II), (III), (IV), (V), (IIIM), (IVM), (VM), (IIIN), (IVN), (VN), (VI), (VII-1), (VII-2), (VII-3), (VII-4), and (VIII).

[0283] The active compound can be formulated in a form suitable for administration via any appropriate route, either in a unit dose or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0284] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0285] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0286] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0287] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0288] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0289] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0290] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0291] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0292] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0293] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0294] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0295] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0296] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0297] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0298] Terminology Explanation

[0299] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0300] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-10 Alkyl groups, in some embodiments having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0301] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene has 1 to 10 carbon atoms (i.e., C10). 1-10 alkylene), C 1-8 Alkylene, C 2-7 Alkylene or C 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker.

[0302] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0303] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 (Alynyl group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0304] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0305] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3 to 10-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4 to 7-membered cycloalkyl group), or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 5 or 6 ring atoms.

[0306] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0307] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0308] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0309] Its connection point can be anywhere; wait.

[0310] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0311] Its connection point can be anywhere; wait.

[0312] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0313] Its connection point can be anywhere.

[0314] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... wait.

[0315] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0316] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group has heterocyclic groups with 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclic groups), heterocyclic groups with 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclic groups), and heterocyclic groups with 7 to 10 ring atoms (i.e., 7 to 10-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic groups), 4 to 7 ring atoms (i.e., 4 to 7-membered heterocyclic groups), or 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 5 or 6 ring atoms.

[0317] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, azacyclic butyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0318] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0319] "Nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one (e.g., 1, 2, 3, or 4) nitrogen atoms within its ring, as defined above. In some embodiments, it is a 3- to 12-membered nitrogen-containing heterocyclic group or a 3- to 10-membered nitrogen-containing heterocyclic group; in some embodiments, it is a 4- to 7-membered nitrogen-containing heterocyclic group; and in some embodiments, it is a 5- or 6-membered nitrogen-containing heterocyclic group.

[0320] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes mono-spiroheterocyclic groups and multi-spiroheterocyclic groups (such as bi-spiroheterocyclic groups), and in some embodiments, it is a mono-spiroheterocyclic group or a bi-spiroheterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered mono-spiroheterocyclic group. Non-limiting examples include:

[0321] wait.

[0322] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, it is a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include: wait.

[0323] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0324] wait.

[0325] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include: wait.

[0326] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0327] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 6 to 20-membered aryl). In some embodiments, the aryl group has 6 to 14 ring atoms (i.e., 6 to 14-membered aryl), and in some embodiments, it has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). Monocyclic aryl groups include, for example, phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthracene, phenanthrene, etc. The polycyclic aryl group further includes fusion of a phenyl group with one or more heterocyclic or cycloalkyl groups, or fusion of a naphthyl group with one or more heterocyclic or cycloalkyl groups, wherein the bonding site is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including: wait.

[0328] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0329] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group), in some embodiments it is a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), and in some embodiments it is a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0330] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, pyridine-1-oxide, etc.

[0331] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include: wait.

[0332] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0333] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0334] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0335] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0336] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0337] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0338] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0339] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0340] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0341] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0342] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0343] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0344] The term "hydroxyalkoxy" refers to an alkoxy group that is substituted with one or more hydroxyl groups, where the alkoxy group is as defined above.

[0345] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkyl and alkoxy groups are as defined above; in some embodiments, they are -alkyl-alkoxy groups; including but not limited to methoxymethyl, ethoxymethyl, and methoxyethyl.

[0346] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0347] The term "hydroxyl group" refers to -OH.

[0348] The term "amino" refers to -NH2.

[0349] The term "cyano" refers to -CN.

[0350] The term "nitro" refers to -NO2.

[0351] The term "oxo" or "oxo group" refers to "=O".

[0352] The term "carbonyl" refers to C=O.

[0353] TBS refers to tert-butyldimethylsilyl.

[0354] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), etc.

[0355] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0356] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0357] Two identical atoms or groups on the same side of a double bond or alicyclic ring are cis isomers, also denoted by cis-.

[0358] In the chemical structure of the compound described in this disclosure, express and An equimolar (1:1) mixture.

[0359] The compounds disclosed herein may comprise all of their rotational isomers and conformationally restricted states. They also include transisomers, the term "transisomer" being a stereoisomer resulting from restricted rotation around a single bond, wherein an energy difference attributable to stereostrain or other contributing factors creates a sufficiently high rotational barrier to allow the separation of individual conformational isomers. For example, some of the compounds disclosed herein may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0360] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0361] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0362] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0363] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0364] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0365] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0366] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6"Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0367] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, such as 1, 2, or 3, meaning that 1 to 3 hydrogen atoms are independently replaced by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0368] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0369] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0370] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0371] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0372] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations. Detailed Implementation

[0373] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0374] Example

[0375] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0376] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0377] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector).

[0378] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive).

[0379] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0380] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0381] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0382] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0383] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0384] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0385] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0386] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0387] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, Bailingwei, and Shanghai Bid Pharmaceutical.

[0388] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0389] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0390] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0391] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0392] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0393] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0394] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0395] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0396] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0397] Example 1

[0398] 3-(1'-(1-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)-5,7-difluoro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidin]-6-yl)piperidin-2,6-dione

[0399] first step

[0400] 4-Hydroxy-4-((2,4,6-trifluorophenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester 1c

[0401] 1-Oxa-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester 1a (2.88 g, 13.50 mmol, Adamas reagent) and 2,4,6-trifluorophenol 1b (2.00 g, 13.51 mmol, Shanghai Haohong Biopharmaceutical) were dissolved in 12 mL of N,N-dimethylformamide, and anhydrous potassium carbonate (5.60 g, 40.52 mmol) was added. The mixture was heated to 90 °C and reacted for 16 hours. After the reaction solution cooled to room temperature, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined. The organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1c (3.52 g, yield: 72%).

[0402] MS m / z(ESI):262.2[M-99].

[0403] Step 2

[0404] 5,7-Difluoro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 1d

[0405] Compound 1c (3.2 g, 8.85 mmol) was dissolved in 35 mL of N-methylpyrrolidone, and sodium hydride (678 mg, 17.69 mmol, 60% purity) was added. The reaction was allowed to proceed for 15 minutes, then heated to 120 °C and reacted for 23 hours. After the reaction solution cooled to room temperature, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined. The organic phases were washed with saturated sodium chloride solution (30 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1d (1.45 g, yield: 48%).

[0406] MS m / z(ESI):242.2[M-99].

[0407] Step 3

[0408] 6-Bromo-5,7-difluoro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 1e

[0409] Compound 1d (1.4 g, 4.10 mmol) was dissolved in 18 mL of acetonitrile, and N-bromosuccinimide (1.05 g, 5.90 mmol, Shaoyuan Technology) was added. The mixture was heated to 50 °C and reacted for 12 hours. The solvent was removed by concentration under reduced pressure. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined. The organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the crude product, the title compound. The crude product was purified by high performance liquid chromatography (Shimadzu LC-20AP Prep system, chiral preparative column ChiralPak IG, 50mm*300mm, 10um, (Daicel), elution system: n-hexane:ethanol = 100:10 (v / v), flow rate: 80mL / min). The first component peak (12.078min) was collected and concentrated under reduced pressure to give the title compound 1e (495mg, yield: 29%).

[0410] MS m / z(ESI):320.0[M-99].

[0411] Step 4

[0412] 6-(2,6-bis(benzyloxy)pyridin-3-yl)-5,7-difluoro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 1f

[0413] Weigh compound 1e (60 mg, 0.14 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (60 mg, 0.14 mmol, Bio-Pharmaceutical) into a 50 mL round-bottom flask, add 3 mL of 1,4-dioxane and 1 mL of water, then add [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (10 mg, 0.02 mmol) and anhydrous potassium carbonate (40 mg, 0.29 mmol). Purge with nitrogen three times, heat to 100 °C and react for 16 hours. After the reaction mixture cools to room temperature, add water (10 mL) to the reaction solution, extract with ethyl acetate (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL × 3), and dry with anhydrous sodium sulfate. The residue was filtered, concentrated, and purified by silica gel column chromatography with eluent system B to give title compound 1f (72 mg, yield: 80%).

[0414] MS m / z(ESI): 631.4 [M+1].

[0415] Step 5

[0416] 1g of 6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidin]-1'-carboxylic acid tert-butyl ester

[0417] Compound 1f (72 mg, 0.11 mmol) was dissolved in 5 mL of ethyl acetate. 10% wet palladium on carbon (containing 50% water, 24 mg, 0.22 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 32 mg, 0.23 mmol) were added. The mixture was purged three times with hydrogen, and the temperature was raised to 60 °C for 6 hours under a hydrogen atmosphere. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give 1 g (45 mg, yield: 87%) of the title compound.

[0418] MS m / z(ESI): 451.2 [M-1].

[0419] Step 6

[0420] 3-(5,7-difluoro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-6-yl)piperidine-2,6-dione trifluoroacetate 1h

[0421] 1 g (45 mg, 0.10 mmol) of the compound was dissolved in 3 mL of dichloromethane, and 0.4 mL of trifluoroacetic acid was added dropwise under ice bath conditions. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 1h (46 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0422] MS m / z(ESI): 353.2 [M+1].

[0423] Step 7

[0424] 3-(1'-(1-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)-5,7-difluoro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidin]-6-yl)piperidin-2,6-dione

[0425] (7) 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-oxopiperidin-1-yl)-5 2 5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutazacyclononadenosine-3-one 1i (20 mg, 0.04 mmol, prepared by the method disclosed in intermediate 25 on page 89 of patent application "WO2024099395A1") and compound 1h (46 mg, 0.10 mmol) were dissolved in 3 mL of 1,2-dichloroethane, and N,N-diisopropylethylamine (25 mg, 0.19 mmol) and sodium tri(acetoxy)borohydride (27 mg, 0.13 mmol) were added. The mixture was purged with nitrogen three times and the temperature was raised to 50 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 35%-60%, flow rate: 30 mL / min) to give title compound 1 (7.9 mg, yield: 24%).

[0426] MS m / z(ESI): 862.4 [M+1].

[0427] 1 H NMR (500MHz, DMSO-d6): δ12.34(s,1H),10.93(s,1H),8.65(s,1H),7.89(s,1H),7.46(s,1H ),7.33(d,1H),7.01(d,1H),6.91(dd,1H),6.73(dd,1H),4.64(d,2H),4.37-3.89(m,6H),3. 76-3.69(m,5H),2.94-2.87(m,2H),2.83-2.76(m,1H),2.74-2.61(m,5H),2.59-2.51(m,8H) ,2.48-2.39(m,2H),2.14-2.06(m,1H),1.89-1.86(m,2H),1.76-1.67(m,4H),1.60(qd,2H).

[0428] Example 2

[0429] 3-(1'-(1-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)piperidin-2,6-dione

[0430] first step

[0431] 4-(bromomethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2b

[0432] 10 g (46.89 mmol, Bio-Tech Pharmaceuticals) of tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid 2a was weighed into a 500 mL flask. 300 mL of dichloromethane was added, and the mixture was cooled in an ice bath. Triphenylphosphine (16 g, 61.00 mmol) and carbon tetrabromide (20.2 g, 60.91 mmol) were then added, and the reaction was continued in an ice bath for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 2b (6.3 g, yield: 49%).

[0433] Step 2

[0434] 4-((2,4-difluoro-6-iodophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2c

[0435] Compound 2b (1.13 g, 4.09 mmol) and 2,4-difluoro-6-iodophenol (800 mg, 3.12 mmol, Bailingwei Chemical) were weighed into a 100 mL flask. 20 mL of N,N-dimethylformamide and anhydrous potassium carbonate (864 mg, 6.25 mmol) were added, and the mixture was reacted for 30 minutes. A saturated ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined. The organic phase was washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2c (1.0 g, yield: 71%).

[0436] MS m / z(ESI):396.0[M-55].

[0437] Step 3

[0438] 5,7-Difluoro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 2d

[0439] Compound 2c (700 mg, 1.55 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and palladium acetate (70 mg, 0.31 mmol, Bioderm Pharmaceuticals), sodium formate (317 mg, 4.66 mmol, Adamas reagent), sodium acetate (382 mg, 4.65 mmol), and tetraethylammonium chloride (772 mg, 4.66 mmol) were added. The mixture was purged with nitrogen three times and heated to 90 °C for 12 hours. The reaction solution was cooled to room temperature, and saturated ammonium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 2d (400 mg, yield: 80%).

[0440] MS m / z(ESI):268.0[M-55].

[0441] Step 4

[0442] 5,7-Difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 2e

[0443] Compound 2d (700 mg, 2.17 mmol) was dissolved in 20 mL of methanol, and 10% wet palladium on carbon (containing 50% water, 231 mg, 2.17 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 305 mg, 2.17 mmol) were added. The mixture was purged three times with hydrogen and reacted under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2e (350 mg, yield: 50%).

[0444] MS m / z(ESI):270.1[M-55].

[0445] Step 5

[0446] 5,7-Difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 2f

[0447] Compound 2e (350 mg, 1.08 mmol) was dissolved in 20 mL of tetrahydrofuran. The mixture was cooled to -78 °C in a dry ice-ethanol bath, and diisopropylaminolithium (0.81 mL, 1.62 mmol, Adamas reagent) was slowly added dropwise. The reaction was carried out at -78 °C for 2 hours. Iodine (547 mg, 2.15 mmol) was then added, and the mixture was slowly heated to room temperature and reacted for 3 hours. Saturated sodium thiosulfate solution (10 mL) and saturated sodium carbonate solution (10 mL) were added to the reaction solution. The mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL × 3). The solution was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2f (450 mg, yield: 93%).

[0448] MS m / z(ESI):396.0[M-55].

[0449] 1 H NMR (500MHz, CDCl3): δ6.67(d,1H),4.52(s,2H),4.12-4.07(m,2H),2.87(m,2H),1.78-1.73(m,4H),1.46(s,9H).

[0450] Step 6

[0451] 2g of 6-(2,6-bis(benzyloxy)pyridin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester

[0452] Compound 2f (450 mg, 0.99 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (417 mg, 0.99 mmol) were dissolved in 10 mL of 1,4-dioxane and 2 mL of water. Then, [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (65 mg, 0.10 mmol) and anhydrous potassium carbonate (414 mg, 2.99 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give 2 g (581 mg, yield: 95%) of the title compound. MS m / z (ESI): 615.2 [M+1].

[0453] Step 7

[0454] 6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 2h

[0455] 2 g (90 mg, 0.15 mmol) of the compound was dissolved in 5 mL of ethyl acetate, and then 10% wet palladium on carbon (containing 50% water, 24 mg, 0.23 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 32 mg, 0.228 mmol) were added. The mixture was purged three times with hydrogen, and the temperature was raised to 60 °C for 6 hours under a hydrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 2h (40 mg, yield: 62%).

[0456] MS m / z(ESI):381.1[M-55].

[0457] Step 8

[0458] 3-(5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)piperidin-2,6-dione trifluoroacetate 2i

[0459] Compound 2h (40 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane, and 0.4 mL of trifluoroacetic acid was added dropwise under ice bath conditions. The reaction mixture was then reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 2i (40 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0460] MS m / z(ESI): 337.3 [M+1].

[0461] Step 9

[0462] 3-(1'-(1-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)piperidin-2,6-dione

[0463] Compound 1i (20 mg, 0.04 mmol) and compound 2i (31 mg, 0.07 mmol) were dissolved in 3 mL of 1,2-dichloroethane, followed by the addition of N,N-diisopropylethylamine (25 mg, 0.19 mmol) and sodium tri(acetoxy)borohydride (27 mg, 0.13 mmol). The mixture was purged with nitrogen three times and the reaction was carried out at 50 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 35%-60%, flow rate: 30 mL / min) to give title compound 2 (2.7 mg, yield: 11%).

[0464] MS m / z(ESI): 846.4 [M+1].

[0465] 1 H NMR (500MHz, DMSO-d6): δ12.34(s,1H)10.94(s,1H),8.66(s,1H),7.90(s,1H),7.47(s,1H),7 .35(d,1H),7.13(d,1H),7.01(s,1H),6.92(d,1H),4.68-4.50(m,4H),4.22-4.08(m,4H),3.7 6-3.64(m,5H),2.94-2.87(m,2H),2.83-2.76(m,1H),2.74-2.61(m,5H),2.59-2.51(m,8H),2 .48-2.39(m,2H),2.14-2.06(m,1H),1.90-1.86(m,2H),1.73-1.67(m,4H),1.66-1.58(m,2H).

[0466] Example 3

[0467] 3-((S)-3-((4-(1-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6-yl)piperidin-4-yl)piperazin-1-yl)methyl)-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)piperidin-2,6-dione

[0468] first step

[0469] 3-Bromo-2,4-difluoro-6-hydroxybenzaldehyde 3b

[0470] Weigh 2.5 g (11.96 mmol, Bio-Tech Pharmaceuticals) of 4-bromo-3,5-difluorophenol 3a into a 250 mL round-bottom flask, add 60 mL of acetonitrile and anhydrous magnesium chloride (6.4 g, 35.96 mmol), react for 10 min, add triethylamine (3 g, 29.63 mmol), react for 20 min, add paraformaldehyde (1.8 g, 59.95 mmol), and react at 80 °C for 16 h. Cool the reaction solution to room temperature, add 2 M hydrochloric acid (50 mL), stir for 1 h, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash the organic phase with saturated sodium chloride solution (50 mL × 2), and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to give title compound 3b (900 mg, yield: 31%).

[0471] Step 2

[0472] 6-(benzyloxy)-3-bromo-2,4-difluorobenzaldehyde 3c

[0473] Compound 3b (9.87 g, 41.65 mmol) was dissolved in 100 mL of N,N-dimethylformamide, and anhydrous potassium carbonate (11.6 g, 83.93 mmol) and benzyl bromide (7.83 g, 45.78 mmol) were added. The mixture was heated to 80 °C and reacted for 1 hour. The reaction solution was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed successively with water (50 mL × 2) and saturated sodium chloride solution (100 mL × 2). The solution was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3c (9.7 g, yield: 71%).

[0474] Step 3

[0475] 6-(benzyloxy)-3-bromo-2,4-difluorophenol 3d

[0476] Compound 3c (1.06 g, 3.24 mmol) was dissolved in 20 mL of dichloromethane, and m-chloroperoxybenzoic acid (1.65 g, 8.13 mmol, 85% purity) was added. The reaction mixture was reacted for 16 hours. A saturated sodium sulfite solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with a saturated sodium bicarbonate solution (20 mL × 2). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3d (1.2 g, yield: 71%).

[0477] MS m / z(ESI):313.0[M-1].

[0478] Step 4

[0479] 2-((6-(benzyloxy)-3-bromo-2,4-difluorophenoxy)methyl)oxapropane 3e

[0480] Compound 3d (1.2 g, 2.67 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and 2-(chloromethyl)oxapropane (370 mg, 4.00 mmol) and sodium hydride (215 mg, 5.37 mmol, 60% purity) were added. The mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3e (570 mg, yield: 57%).

[0481] MS m / z(ESI): 369.1 [M-1].

[0482] Step 5

[0483] 4-Bromo-2-(2-chloro-3-hydroxypropoxy)-3,5-difluorophenol 3f

[0484] Compound 3e (565 mg, 1.52 mmol) was dissolved in 5 mL of 4 M hydrogen chloride in a 1,4-dioxane solution, and concentrated hydrochloric acid (10 mL) was added. The mixture was heated to 100 °C and reacted for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give the crude product, title compound 3f (483 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0485] MS m / z(ESI): 314.9 [M-1].

[0486] Step 6

[0487] 3g of (6-bromo-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol

[0488] Compound 3f (483 mg, 1.52 mmol) was weighed into a 50 mL round-bottom flask, 5 mL of 1,4-dioxane and 2.5 mL of ethanol were added, and the mixture was stirred to dissolve. Potassium hydroxide (171 mg, 3.05 mmol) was added, and the mixture was heated to 100 °C and reacted for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 3 g (250 mg, yield: 58%).

[0489] MS m / z(ESI):279.0[M-1].

[0490] Step 7

[0491] (6-(2,6-bis(benzyloxy)pyridin-3-yl)-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol 3h

[0492] Weigh 3 g (1.16 g, 4.13 mmol) of compound and 1.73 g (4.15 mmol) of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine into a 50 mL round-bottom flask. Add 20 mL of 1,4-dioxane and 4 mL of water, purge with nitrogen three times, and heat to 100 °C for 10 min. Add [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (269 mg, 0.41 mmol) and anhydrous potassium carbonate (1.14 g, 8.25 mmol), purge with nitrogen three times, and heat to 100 °C for 16 h. Cool the reaction solution to room temperature, add water (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), and dry with anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3h (1.5 g, yield: 74%).

[0493] MS m / z(ESI):492.2[M+1].

[0494] Step 7 ((2R)-6-(2,6-bis(benzyloxy)pyridin-3-yl)-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol 3h-1

[0495] ((2S)-6-(2,6-bis(benzyloxy)pyridin-3-yl)-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol3h-2

[0496] Compound 3h (1.5 g) was chirally separated (separation conditions: Gilson-281, column: CHIRALPAK OD-H (20×250 mm), mobile phase: n-hexane / ethanol (containing 0.5% ammonia (NH3)) = 95 / 5 (v / v), flow rate 20 mL / min) to obtain compounds 3h-1 (480 mg) and 3h-2 (510 mg).

[0497] 3h-1: Single-configuration compounds (shorter retention time):

[0498] MS m / z(ESI):492.2[M+1].

[0499] Chiral HPLC analysis method: retention time 7.96 min (Agilent 1260 DAD, column: CHIRALCEL OD-H (4.6×150 mM), 5 μm; mobile phase: n-hexane / ethanol (containing 0.1% diethylamine) = 90 / 10 (v / v)), flow rate 1 mL / min);

[0500] 3h-2: Single-configuration compounds (longer retention time):

[0501] MS m / z(ESI):492.2[M+1].

[0502] Chiral HPLC analysis method: retention time 8.85 min (Agilent 1260 DAD, column: CHIRALCEL OD-H (4.6 × 150 mM), 5 μm; mobile phase: n-hexane / ethanol (containing 0.1% diethylamine) = 90 / 10 (v / v)), flow rate 1 mL / min).

[0503] Step 8

[0504] 3-((S)-5,7-difluoro-2-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)piperidine-2,6-dione 3i

[0505] Compound 3h-2 (480 mg, 0.98 mmol) was dissolved in 20 mL of ethyl acetate, and 10% wet palladium on carbon (containing 50% water, 100 mg, 0.94 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 100 mg, 0.71 mmol) were added. The mixture was purged with hydrogen three times, and the temperature was raised to 60 °C for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 3i (282 mg, yield: 92%). The crude product was used directly in the next reaction without purification.

[0506] MS m / z(ESI):312.0[M-1].

[0507] Step 9

[0508] (2R)-6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-2-formaldehyde 3j

[0509] Compound 3i (282 mg, 0.90 mmol) was dissolved in 16 mL of ethyl acetate, and 2-iodobenzoic acid (378 mg, 1.35 mmol) was added. The reaction was carried out for 20 minutes, and then heated to 60 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 3j (270 mg, yield: 96%). The crude product was used directly in the next reaction without purification.

[0510] MS m / z(ESI):310.0[M-1].

[0511] Step 10

[0512] 4-(1-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 3l)piperidine-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0513] (7) 1 s,7 3 s,E)-5 6 -bromo-1 1 ,2 6 -Dimethyl-5 2 5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclobutazine-3-one 3k (100 mg, 0.20 mmol, prepared by the method disclosed in intermediate 1 on page 72 of patent application “WO2024099395A1”), 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.74 mmol) dissolved in 5 mL N,N-Dimethylacetamide was added to tridibenzylacetone dipalladium (18 mg, 0.02 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (18 mg, 0.04 mmol), and sodium tert-butoxide (100 mg, 1.04 mmol). The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 3l (115 mg, yield: 84%). MS m / z (ESI): 696.4 [M+1].

[0514] Step 11

[0515] (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-(piperazin-1-yl)piperidin-1-yl)-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaza-1(4,5)-pyrazola-7(1,3)-cyclobutanecyclononafen-3-one hydrochloride 3m

[0516] Compound 3l (110 mg, 0.16 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of 4 M hydrogen chloride solution in 1,4-dioxane was added. The reaction mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 3m (106 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0517] MS m / z(ESI): 596.3 [M+1].

[0518] Step Twelve

[0519] 3-((S)-3-((4-(1-((7 1 s,7 3 s,E)-1 1 ,2 6-Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)piperazin-1-yl)methyl)-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)piperidin-2,6-dione

[0520] Compound 3m (33 mg, 0.05 mmol) was dissolved in 3 mL of 1,2-dichloroethane, and N,N-diisopropylethylamine (50 mg, 0.39 mmol) was added. The reaction was allowed to proceed for 5 minutes, followed by the addition of compound 3j (30 mg, 0.10 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol). The mixture was then heated to 50 °C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (Wasters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 35%-60%, flow rate: 30 mL / min) to give title compound 3 (7 mg, yield: 16%).

[0521] MS m / z(ESI): 891.4 [M+1].

[0522] 1 H NMR (500MHz, DMSO-d6): δ12.40(s,1H),10.93(s,1H),8.66(s,1H),7.90(s,1H),7.47(s,1H),7.34(d,1H),7.02 (d,1H),6.90(dd,1H),6.75(dd,1H),4.91-4.49(m,3H),4.48-4.42(m,1H),4.38(dd,1H),4.31-4.09(m,3H),4. 05-4.02(m,2H),3.72(s,5H),3.51-3.39(m,2H),3.06-2.85(m,3H),2.85-2.75(m,1H),2.74-2.64(m,3H),2.63 -2.53(m,10H),2.35-2.27(m,1H),2.17-2.05(m,2H),2.03-1.95(m,2H),1.93-1.82(m,2H),1.61-1.49(m,2H).

[0523] Example 4

[0524] 3-((R)-2-((4-(1-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)piperazin-1-yl)methyl)-5,7-difluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)piperidin-2,6-dione

[0525] Using the method of Example 3, the starting compound 3h-2 in step 9 was replaced with 3h-1, and purified by high performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 35%-60%, flow rate: 30 mL / min) to obtain title compound 4 (7.5 mg, yield: 17%). MS m / z (ESI): 891.4 [M+1].

[0526] 1 H NMR (500MHz, DMSO-d6): δ12.40(s,1H),10.93(s,1H),8.66(s,1H),7.90(s,1H),7.47(s,1H),7.34(d,1H),7.02 (d,1H),6.90(dd,1H),6.75(dd,1H),4.91-4.49(m,3H),4.48-4.42(m,1H),4.38(dd,1H),4.31-4.09(m,3H),4. 05-4.02(m,2H),3.72(s,5H),3.51-3.39(m,2H),3.06-2.85(m,3H),2.85-2.75(m,1H),2.74-2.64(m,3H),2.63 -2.53(m,10H),2.35-2.27(m,1H),2.17-2.05(m,2H),2.03-1.95(m,2H),1.93-1.82(m,2H),1.61-1.49(m,2H).

[0527] Example 5

[0528] 3-((R)-3-(1-((7 1 s,73 S,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)-7,9-difluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-2,6-dione 5

[0529] first step

[0530] 1-Benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester 5b

[0531] (R)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester 5a (3.0 g, 13.90 mmol, Shanghai Shaoyuan) was dissolved in ethyl acetate (25 mL), water (25 mL) was added, the mixture was cooled to 0 °C, sodium bicarbonate (3.5 g, 41.70 mmol) was added, and benzyl chloroformate (3.55 g, 20.80 mmol) was added dropwise. The reaction mixture was reacted for 16 hours. The reaction solution was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 5b (4.3 g, yield: 88%).

[0532] MS m / z(ESI): 349.2 [M-1].

[0533] Step 2

[0534] 1-Benzyl 4-(tert-butyl)(R)-2-((2,4,6-trifluorophenoxy)methyl)piperazine-1,4-dicarboxylic acid ester 5c

[0535] 2,4,6-Trifluorophenol (700 mg, 4.7 mmol) and compound 5b (1.68 g, 4.78 mmol) were added to tetrahydrofuran (50 mL), and triphenylphosphine (2.45 g, 9.34 mmol) and diisopropyl azodicarbonate (1.89 g, 9.35 mmol) were added under nitrogen atmosphere. The mixture was reacted at room temperature under nitrogen atmosphere for 16 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 5c (2.3 g, yield: 100%).

[0536] MS m / z(ESI):425.2[M-55].

[0537] Step 3

[0538] (R)-3-((2,4,6-trifluorophenoxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 5d

[0539] Compound 5c (2.3 g, 4.79 mmol) was dissolved in methanol (40 mL), and 10% wet palladium on carbon (containing 50% water, 100 mg) and 20% wet palladium hydroxide on carbon (containing 50% water, 100 mg) were added. The mixture was purged with hydrogen three times and reacted for 16 hours. The solution was filtered and concentrated under reduced pressure to remove the solvent, yielding the crude product, title compound 5d (1.86 g, yield: 100%). The crude product was used directly in the next reaction without purification.

[0540] MS m / z(ESI): 347.2 [M+1].

[0541] Step 4

[0542] (R)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 5e

[0543] Compound 5d (1.76 g, 5.08 mmol) was dissolved in dimethyl sulfoxide (40 mL), and sodium hydride (230 mg, 5.75 mmol, 60% purity) was added. The reaction was carried out for 30 minutes, and then heated to 120 °C and reacted for another 30 minutes. The reaction was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 5e (340 mg, yield: 21%).

[0544] MS m / z(ESI):271.2[M-55].

[0545] Step 5

[0546] (R)-8-bromo-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 5f

[0547] Compound 5e (155 mg, 475 μmol) was dissolved in dichloromethane (7.5 mL), and N-bromosuccinimide (95 mg, 533.8 μmol) was added at room temperature. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 5f (148 mg, yield: 77%). MS m / z (ESI): 349.0 [M-55].

[0548] Step 6

[0549] (4aR)-8-(2,6-bis(benzyloxy)pyridin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 5g

[0550] Compound 5f (148 mg, 0.365 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (155 mg, 371.4 μmol) were dissolved in 6.5 mL of a mixture of 1,4-dioxane and water (V / V = 10 / 3). [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (26 mg, 0.040 μmol) and anhydrous potassium carbonate (116 mg, 0.839 mmol) were added. The reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the water in the reaction solution (20 mL) was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give 5 g (160 mg, yield: 71%) of the title compound.

[0551] MS m / z(ESI): 616.2 [M+1].

[0552] Step 7

[0553] (4aR)-8-(2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 5h

[0554] 5 g (160 mg, 0.260 mmol) of the compound was dissolved in ethyl acetate (10 mL), and 10% wet palladium on carbon (containing 50% water, 30 mg) and 20% wet palladium hydroxide on carbon (containing 50% water, 40 mg) were added. The mixture was purged with hydrogen three times, and the temperature was raised to 60 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5 h (113 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0555] Step 8

[0556] 3-((R)-7,9-difluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidine-2,6-dione trifluoroacetate 5i

[0557] Compound 5h (113 mg, 0.258 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added at room temperature. The reaction was allowed to proceed for 2 hours. The solvent was removed under reduced pressure to give the crude product, title compound 5i (116 mg, yield: 100%). MS m / z (ESI): 338.2 [M+1].

[0558] Step 9

[0559] 3-((R)-3-(1-((7 1 s,7 3 S,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclobutanecyclononazol-5 6 -yl)piperidin-4-yl)-7,9-difluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-2,6-dione 5

[0560] Compound 1i (40 mg, 0.076 mmol) and compound 5i (103.0 mg, 0.228 mmol) were added to 1,2-dichloroethane (5 mL), followed by diisopropylethylamine (100 mg, 0.774 mmol) and sodium triacetoxyborohydride (50 mg, 235.9 μmol). The reaction mixture was reacted at 40 °C for 16 h. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 20%-80%, flow rate: 30 mL / min) to give title compound 5 (14 mg, yield: 21%).

[0561] MS m / z(ESI): 847.3 [M+1].

[0562] 1 H NMR (500MHz, DMSO-d6): δ12.41(s,1H),10.89(s,1H),8.66(s,1H),7.90(s,1H),7.47(s,1H),7.35(d,1H),7.03( d,1H),6.92(dd,1H),6.67(d,1H),4.85-4.43(m,3H),4.36(dd,1H),4.32-4.10(m,2H),4.07(dd,1H),3.92(t,1H) ,3.82-3.67(m,5H),3.42-3.34(m,2H),3.33-2-3.26(m,2H),3.17-3.08(m,1H),3.08-2.96(m,2H),2.97-2.85(m, 2H),2.84-2.66(m,4H),2.56(s,3H),2.47-2.30(m,3H),2.14-2.04(m,1H),2.04-1.85(m,4H),1.65-1.53(s,2H).

[0563] Example 6

[0564] 3-((R)-3-(1-((7 1 R,7 3 S,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6-yl)piperidin-4-yl)-7,9-difluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-2,6-dione

[0565] Using the method of Example 5, the raw material compound 1i in step nine was replaced with (7) 1 R,7 3 S,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-oxopiperidin-1-yl)-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclopentacyclononafen-3-one 6a (prepared by the method disclosed in the specification on page 136 of patent application "WO2024246838A1, intermediate 64") was purified by high performance liquid chromatography (Gilson GX-281, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-65%, flow rate: 30 mL / min) to give title compound 6 (2.8 mg, yield: 10%).

[0566] MS m / z(ESI): 861.4 [M+1].

[0567] 1 H NMR(500 MHz, DMSO-d6): δ12.43(s,1H),10.89(s,1H),8.53(s,1H),7.90(s,1H),7.45(s,1H),7.37(d,1H),7.03(s,1 H),6.93(d,1H),6.68(d,1H),4.39-4.27(m,2H),4.22-4.17(m,1H),4.11-4.04(m,2H),3.97-3.91(m,1H),3 .79-3.72(s,4H),3.33(s,3H),3.16-3.11(m,1H),3.07-2.97(m,2H),2.84-2.67(m,4H),2.65-2.54(m,5H), 2.47-2.31(m,3H),2.19(t,1H),2.11-1.88(m,6H),1.88-1.74(m,3H),1.64-1.56(m,2H),1.50-1.44(m,1H).

[0568] Example 7

[0569] 3-((R)-7,9-difluoro-3-(1-((7 1 R,7 3 S)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-2,6-dione 7

[0570] Using the method of Example 5, the raw material compound 1i in step nine was replaced with (7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(4-oxopiperidin-1-yl)-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-3-one 7a (prepared by the method disclosed in patent application "Intermediate 101 on page 154 of patent application "WO2024246838A1") was purified by high performance liquid chromatography (GILSON 306, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-95%, flow rate: 30 mL / min) to give title compound 7 (28 mg, yield: 35%).

[0571] MS m / z(ESI): 875.4 [M+1].

[0572] 1H NMR (500MHz, DMSO-d6): δ12.43(s,1H),10.89(s,1H),8.54(s,1H),7.46(s,1H),7.36(d,1H),7.03(s, 1H),6.93(d,1H),6.67(d,1H),4.41-4.27(m,2H),4.23-4.16(m,1H),4.14-3.96(m,3H),3.95-3.89(m ,1H),3.81-3.71(m,3H),3.67(s,3H),3.16-3.10(m,1H),3.07-2.98(m,2H),2.83-2.65(m,5H),2.64- 2.54(m,5H),2.48(s,3H),2.43-2.29(m,2H),2.13-2.06(m,1H),2.05-1.68(m,9H),1.65-1.52(m,3H).

[0573] Examples 8-1 and 8-2

[0574] 3-((6aR,8R)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-1

[0575] 3-((6aR,8S)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-56 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-2

[0576] first step

[0577] (R)-7-((2,4,6-trifluorophenoxy)methyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylic acid benzyl ester 8b

[0578] 2,4,6-Trifluorophenol (600 mg, 4.05 mmol, Shanghai Haohong Biopharmaceutical), (R)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylic acid benzyl ester 8a (1.24 g, 4.03 mmol, prepared by the method disclosed in the patent application "Intermediate FU" on page 325 of the specification on WO2019183367A1) were dissolved in tetrahydrofuran (20 mL). Under ice bath cooling, triphenylphosphine (2.12 g, 8.08 mmol) and diisopropyl azodicarbonate (1.64 g, 8.11 mmol) were added, and the reaction was carried out for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 8b (1.7 g, yield: 99%).

[0579] MS m / z(ESI):438.2[M+1].

[0580] Step 2

[0581] (R)-7-((2,4,6-trifluorophenoxy)methyl)-1,4-dioxa-8-azaspiro[4.5]decane8c

[0582] Compound 8b (1.75 g, 4.00 mmol) was dissolved in ethyl acetate (50 mL), and 10% wet palladium on carbon (containing 50% water, 175 mg, 1.64 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 175 mg, 1.24 mmol) were added. The mixture was purged three times with hydrogen and reacted under a hydrogen atmosphere for 16 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 8c (1.2 g, yield: 99%). The crude product was used directly in the next reaction without purification.

[0583] MS m / z(ESI): 304.2 [M+1].

[0584] Step 3

[0585] (R)-2,4-Difluoro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyridino[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]8d

[0586] Compound 8c (1.1 g, 3.63 mmol) was dissolved in tetrahydrofuran (20 mL), and bis(trimethylsilylaminolithium) (1 mol / L tetrahydrofuran solution, 4.72 mmol) was added dropwise. The reaction mixture was allowed to react for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 8d (310 mg, yield: 30%).

[0587] MS m / z(ESI):284.2[M+1].

[0588] Step 4

[0589] (R)-3-bromo-2,4-difluoro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyridino[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]8e

[0590] Compound 8d (270 mg, 0.95 mmol) was dissolved in dichloromethane (10 mL), cooled in an ice bath, and N-bromosuccinimide (170 mg, 0.95 mmol) was added. The reaction mixture was reacted for 20 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 8e (347 mg, yield: 99%). MS m / z (ESI): 362.0 [M+1].

[0591] Step 5

[0592] (6aR)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-2,4-difluoro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]8f

[0593] Compound 8e (172 mg, 0.47 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (198 mg, 0.47 mmol) were dissolved in 6.5 mL of a mixture of 1,4-dioxane and water (V / V = 10 / 3). [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (62 mg, 0.09 mmol) and anhydrous potassium carbonate (200 mg, 1.45 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8f (175 mg, yield: 64%).

[0594] MS m / z(ESI): 573.2 [M+1].

[0595] Step 6

[0596] 3-((R)-2,4-difluoro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-3-yl)piperidine-2,6-dione 8g

[0597] Compound 8f (175 mg, 0.30 mmol) was dissolved in ethyl acetate (10 mL), and 10% wet palladium on carbon (containing 50% water, 30 mg, 0.28 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 30 mg, 0.21 mmol) were added. The mixture was purged three times with hydrogen, and the temperature was raised to 60 °C for 16 hours under a hydrogen atmosphere. After the reaction solution cooled to room temperature, it was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 8 g (120 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0598] MS m / z(ESI):395.0[M+1].

[0599] Step 7

[0600] 3-((R)-2,4-difluoro-8-oxo-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione8h

[0601] 8 g (148 mg, 0.37 mmol) of compound was dissolved in 0.25 mL of 1,4-dioxane, and 1 mL of 12 M hydrochloric acid was added. The reaction mixture was reacted for 6 hours. The reaction solution was cooled in an ice bath, and 20 mL of saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to 8. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed successively with 20 mL of water and 20 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 8h (110 mg, yield: 84%). The crude product was used directly in the next reaction without purification.

[0602] MS m / z(ESI): 349.1 [M-1].

[0603] Step 8

[0604] 3-((6aR,8R)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-1

[0605] 3-((6aR,8S)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-2

[0606] (7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(piperazine-1-yl)-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclopentazon-3-one trifluoroacetate 8i (245 mg, 0.22 mmol), prepared by the method disclosed in the specification on page 99 of patent application "WO2024246838A1, intermediate 2", compound 8h (80 mg, 0.23 mmol) was added to 1,2-dichloroethane (5 mL), followed by diisopropylethylamine (295 mg, 2.28 mmol) and sodium triacetoxyborohydride (145 mg, 0.68 mmol), and the mixture was heated to 40 °C and reacted for 16 hours. The reaction solution was filtered and purified by high performance liquid chromatography (Waters-2545, elution system: 0.1% ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 50%-95%, flow rate: 30 mL / min) to give the title compound (15 mg, yield: 7%) and (12 mg, yield: 6%).

[0607] 8-1 or 8-2: Shorter retention time compound (15 mg, retention time 15.47 min): MS m / z (ESI): 875.5 [M+1].

[0608] 1 H NMR (500MHz, DMSO-d6): δ12.43(s,1H),10.89(s,1H),8.54(s,1H),7.46(s,1H),7.37(d,1H),7. 03(s,1H),6.92(dd,1H),6.71(d,1H),4.32(dd,2H),4.25-4.15(m,2H),4.14-4.05(m,3H),3.98- 3.90(m,2H),3.67(s,3H),3.19-3.12(m,5H),2.88-2.76(m,2H),2.71-2.60(m,6H),2.59-2.54( m,4H),2.48(s,3H),2.13-2.00(m,1H),1.98-1.92(m,5H),1.90-1.72(m,4H),1.52-1.44(m,2H).

[0609] The retention time under the preparation conditions was 15.47 min (Waters-2545, column: Welch Ultimate (30×250 mm), 5 μm; elution system: 0.1% ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 50%-95%, flow rate: 30 mL / min);

[0610] 8-2 or 8-1: Compounds with longer retention times (12 mg, retention time 20.91 min): MS m / z (ESI): 875.5 [M+1].

[0611] 1 H NMR (500MHz, DMSO-d6): δ12.41(s,1H),10.88(s,1H),8.53(s,1H),7.45(s,1H),7.38(d,1H),7.0 1(d,1H),6.91(dd,1H),6.59(d,1H),4.41-4.25(m,2H),4.22-4.14(m,1H),4.10-3.94(m,3H),3.9 0(t,1H),3.66(s,3H),3.50-3.41(m,2H),3.18(s,4H),2.92-2.87(m,1H),2.82-2.72(m,2H),2.70 -2.58(m,5H),2.55(s,4H),2.48(s,3H),2.23-1.92(m,5H),1.90-1.52(m,6H),1.39-1.24(m,2H).

[0612] The retention time under the preparation conditions was 20.91 min (Waters-2545, column: Welch Ultimate (30×250 mm), 5 μm; elution system: 0.1% ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 50%-95%, flow rate: 30 mL / min).

[0613] Examples 8-1-1, 8-2-1

[0614] (R)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 --Trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-1-1 and

[0615] (R)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 --Trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-2-1

[0616] first step

[0617] (R)-3-((R)-2,4-difluoro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-3-yl)piperidine-2,6-dione 8j and

[0618] (S)-3-((R)-2,4-difluoro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyridino[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-3-yl)piperidin-2,6-dione 8k

[0619] Compound 8 g (4.37 g) was chirally resolved (separation conditions: Gilson-281, column: CHIRALPAK IG (20×250 mm), 10 μm, mobile phase: acetonitrile / (ethanol / dichloromethane = 95 / 5 (v / v)) = 40 / 60 (v / v), flow rate 20 mL / min) to give title compound 8j (1.36 g, yield: 62%) and 8k (1.62 g, yield: 74%).

[0620] 8j: Single configuration compound, short retention time (3.49 minutes):

[0621] MS m / z(ESI): 395.2 [M+1].

[0622] Chiral HPLC analysis method: retention time 3.49 min (Agilent 1260 DAD, column: CHIRALPAK IG (4.6×150 mM), 5 μm; mobile phase: acetonitrile / ethanol (containing 0.1% diethylamine) = 40 / 60 (v / v), flow rate 1 mL / min);

[0623] 8k: Single configuration compound, relatively long retention time (7.64 minutes):

[0624] MS m / z(ESI): 395.2 [M+1].

[0625] Chiral HPLC analysis method: retention time 7.64 min (Agilent 1260 DAD, column: CHIRALPAK IG (4.6 × 150 mM), 5 μm; mobile phase: acetonitrile / ethanol (containing 0.1% diethylamine) = 40 / 60 (v / v)), flow rate 1 mL / min).

[0626] Step 2

[0627] (R)-3-((R)-2,4-difluoro-8-oxo-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8l

[0628] Compound 8j (1.0 g, 2.54 mmol) was dissolved in 12 M hydrochloric acid (10 mL) and reacted for 24 hours. 6 mL of 12 M hydrochloric acid was added, and the reaction continued for another 4 hours until complete. The reaction solution was cooled in an ice bath, diluted with water (30 mL), and the pH was adjusted to 8 with solid sodium bicarbonate. The solution was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The solution was washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 8l (819 mg, yield: 92%). The crude product was used directly in the next reaction without purification.

[0629] MS m / z(ESI):351.1[M+1].

[0630] Step 3

[0631] (R)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-11 ,1 3 ,2 6 --Trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-1-1 and

[0632] (R)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-2-1

[0633] Compound 8i (2.26 g, 2.03 mmol) was dissolved in 1,2-dichloroethane (60 mL), and diisopropylethylamine (2.51 g, 19.4 mmol) was added. The reaction was allowed to proceed for 10 minutes, followed by the addition of compound 8l (680 mg, 1.94 mmol). The mixture was then heated to 40 °C and reacted for 16 hours. Sodium triacetoxyborohydride (1.23 g, 5.80 mmol) was added, and the reaction was continued at 40 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added. The mixture was extracted with dichloromethane (30 mL × 3), and the organic phase was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Waters-2555, column: PHS-C18 (50×250mm), 5μm; elution system: 0.1% ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-95%, flow rate: 30mL / min) to give the title compounds 8-2-1 (450mg, yield: 27%) and 8-1-1 (311mg, yield: 18%).

[0634] 8-2-1: Compounds with shorter retention times (450 mg, retention time 15.47 min under preparation conditions): MS m / z (ESI): 875.5 [M+1].

[0635] 1 H NMR (500MHz, DMSO-d6): δ12.44(s,1H),10.89(s,1H),8.54(s,1H),7.46(s,1H),7.37(d,1H),7. 03(s,1H),6.91(dd,1H),6.71(d,1H),4.32(dd,2H),4.25-4.15(m,2H),4.14-4.05(m,3H),3.98- 3.90(m,2H),3.67(s,3H),3.19-3.12(m,5H),2.88-2.76(m,2H),2.71-2.60(m,6H),2.59-2.54( m,4H),2.48(s,3H),2.13-2.00(m,1H),1.98-1.92(m,5H),1.90-1.72(m,4H),1.52-1.38(m,2H).

[0636] 8-1-1: Compounds with longer retention times (311 mg, retention time 21.58 min under preparation conditions): MS m / z (ESI): 875.5 [M+1].

[0637] 1 H NMR (500MHz, DMSO-d6): δ12.44(s,1H),10.88(s,1H),8.54(s,1H),7.46(s,1H),7.38(d,1H),7. 03(s,1H),6.92(dd,1H),6.60(d,1H),4.32(d,2H),4.22-4.14(m,1H),4.10-3.94(m,3H),3.90(t ,1H),3.66(s,3H),3.50-3.41(m,2H),3.18(s,4H),2.92-2.87(m,1H),2.82-2.72(m,2H),2.70- 2.58(m,5H),2.55(s,4H),2.48(s,3H),2.23-1.92(m,5H),1.90-1.52(m,6H),1.39-1.24(m,2H).

[0638] Examples 8-1-2, 8-2-2

[0639] (S)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 1 R,73 S,E)-1 1 ,1 3 ,2 6 --Trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-1-2

[0640] (S)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 --Trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-2-2

[0641] first step

[0642] (S)-3-((R)-2,4-difluoro-8-oxo-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8m

[0643] Compound 8k (116 mg, 0.29 mmol) was dissolved in 12 M hydrochloric acid (1 mL) and reacted for 24 hours. The reaction solution was cooled in an ice bath, diluted with water (10 mL), and the pH of the reaction solution was adjusted to 8 with solid sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 8m (95 mg, yield: 92%). The crude product was used directly in the next reaction without purification.

[0644] MS m / z(ESI):351.1[M+1].

[0645] Step 2

[0646] (S)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 --Trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-1-2 and

[0647] (S)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 8-2-2

[0648] Compound 8i (56 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane (4 mL), and diisopropylethylamine (110 mg, 0.85 mmol) was added. The reaction was allowed to proceed for 10 minutes, followed by the addition of the crude compound 8m (30 mg, 0.086 mmol) from the previous step. The mixture was then heated to 40 °C and reacted for 16 hours. Sodium triacetoxyborohydride (54 mg, 0.25 mmol) was added, and the reaction was continued at 40 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added. The mixture was extracted with dichloromethane (30 mL × 3), and the organic phase was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Waters-2545, column: Welch Ultimate (30×250mm), 5μm; elution system: 0.1% ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 50%-95%, flow rate: 30mL / min) to give the title compound (5mg, yield: 11%) and (4mg, yield: 9%).

[0649] One of the compounds in 8-1-2 and 8-2-2: a compound with a shorter retention time (5 mg, retention time 15.15 minutes under the preparation conditions):

[0650] MS m / z(ESI): 875.5 [M+1].

[0651] 1 H NMR (500MHz, DMSO-d6): δ12.39(s,1H),10.89(s,1H),8.54(s,1H),7.46(s,1H),7.37(d,1H),7.03(s,1H),6.91 (dd,1H),6.72(d,1H),4.34-4.31(m,2H),4.25-4.15(m,2H),4.08-4.05(m,2H),3.98-3.92(m,2H),3.67(s,3H), 3.33-3.27(m,1H),3.18-3.10(m,5H),2.83-2.74(m,1H),2.71-2.64(m,5H),2.60-2.56(m,5H),2.48(s,3H),2. 13-2.07(m,1H),2.03-1.92(m,4H),1.91-1.76(m,3H),1.70-1.57(m,1H),1.51-1.45(m,2H),1.21-1.14(m,2H).

[0652] One of the compounds in 8-2-2 and 8-1-2: a compound with a longer retention time (4 mg, retention time 20.82 minutes under the preparation conditions):

[0653] MS m / z(ESI): 875.5 [M+1].

[0654] 1 H NMR (500MHz, DMSO-d6): δ12.41(s,1H),10.88(s,1H),8.54(s,1H),7.45(s,1H),7.38(d,1H),7.03(s,1H),6.94(dd,1H),6.6 0(dd,1H),4.33-4.31(m,2H),4.21-4.18(m,2H),4.07-4.04(m,2H),3.92-3.88(m,1H),3.67(s,3H),3.53-3.46(m,1H),3.19( s,4H),2.93-2.90(m,1H),2.82-2.75(m,2H),2.67-2.64(m,4H),2.61-2.56(m,5H),2.48(s,3H),2.46-2.43(m,1H),2.20-2. 17(m,1H),2.12-2.07(m,2H),2.04-1.95(m,3H),1.89-1.82(m,3H),1.74-1.68(m,2H),1.49-1.45(m,1H),1.39-1.33(m,1H).

[0655] Example 9

[0656] 3-((1'-(1-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-5-yl)amino)piperidin-2,6-dione 9

[0657] Compound 7a (40 mg, 0.072 mmol), 3-((1,3-dihydrospiro[indene-2,4'-piperidine]-5-yl)amino)piperidine-2,6-dione hydrochloride 9a (28 mg, 0.089 mmol, prepared by the method disclosed in Example 5 on page 53 of the specification in patent application CN117384165A) were added to 1,2-dichloroethane (4 mL), followed by diisopropylethylamine (57 mg, 0.441 mmol) and sodium triacetoxyborohydride (60 mg, 0.283 mmol). The mixture was reacted at 50 °C for 16 hours, then sodium triacetoxyborohydride (20 mg, 0.094 mmol) was added, and the mixture was reacted at 50 °C for 2 hours. Then, sodium triacetoxyborohydride (20 mg, 0.094 mmol) was added again, and the mixture was reacted for 4 hours until the starting material was almost completely eliminated. The reaction solution was filtered and purified by high performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-75%, flow rate: 30 mL / min) to give title compound 9 (11 mg, yield: 18%).

[0658] MS m / z(ESI): 851.4 [M+1].

[0659] 1 H NMR(500MHz,DMSO-d6)δ12.42(s,1H),10.77(s,1H),8.54(s,1H),7.46(s,1H),7.36(d,1H),7.03( s,1H),6.93-6.88(m,2H),6.53(s,1H),6.45(d,1H),5.55(d,1H),4.42-4.12(m,4H),4.10-4.03(m, 2H),3.74(t,2H),3.68(s,3H),2.83-2.64(m,4H),2.63-2.60(m,6H),2.58-2.52(m,8H),2.48(s,3 H),2.43-2.37(m,1H),2.13-2.08(m,1H),2.04-1.95(m,1H),1.94-1.72(m,6H),1.70-1.51(m,6H).

[0660] Example 10

[0661] 3-((R)-9-fluoro-3-(1-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3-dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-8-yl)piperidin-2,6-dione 10

[0662] first step

[0663] 4-Benzyl 1-(tert-butyl)(R)-2-(((3-bromo-5-fluoropyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylic acid ester 10b

[0664] 4-Benzyl-1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester 10a (5 g, 14.27 mmol, Bio-Tech Pharmaceuticals), 3-bromo-2,5-difluoropyridine (4.2 g, 21.65 mmol, Bio-Tech Pharmaceuticals), and cesium carbonate (9.2 g, 28.24 mmol) were dissolved in N,N-dimethylformamide (60 mL), and the mixture was heated to 60 °C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 10b (6.6 g, yield: 88%). MS m / z (ESI): 524.2 [M+1].

[0665] Step 2

[0666] (R)-3-(((3-bromo-5-fluoropyridin-2-yl)oxy)methyl)piperazine-1-carboxylic acid benzyl ester 10c

[0667] Compound 10b (3.23 g, 6.16 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (50 mL) was added. The mixture was washed with saturated sodium bicarbonate solution (30 mL × 3). The aqueous phase was extracted again with dichloromethane (50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 10c (2.23 g, yield: 85%). The crude product was used directly in the next reaction without purification.

[0668] MS m / z(ESI):424.1[M+1].

[0669] Step 3

[0670] (R)-9-fluoro-1,2,4a,5-tetrahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine-3(4H)-carboxylic acid benzyl ester 10d

[0671] Compound 10c (2.23 g, 5.26 mmol), methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2-amino-1,1'-biphenyl-2-yl)palladium (500 mg, 0.53 mmol), and cesium carbonate (5 g, 15.35 mmol) were dissolved in 1,4-dioxane (40 mL). The mixture was purged with nitrogen three times and heated to 105 °C for 16 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 10d (1.6 g, yield: 89%).

[0672] MS m / z(ESI): 344.2 [M+1].

[0673] Step 4

[0674] (R)-9-fluoro-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine 10e

[0675] Compound 10d (1.6 g, 4.66 mmol) was dissolved in methanol (30 mL), and 10% wet palladium on carbon (containing 50% water, 200 mg, 0.094 mmol) was added. The mixture was purged three times with hydrogen and reacted under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 10e (970 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0676] MS m / z(ESI):210.2[M+1].

[0677] Step 5

[0678] (R)-9-fluoro-1,2,4a,5-tetrahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10f

[0679] Compound 10e (970 mg, 4.64 mmol) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (1.52 g, 6.96 mmol), triethylamine (1 g, 9.88 mmol), and 4-dimethylaminopyridine (50 mg, 0.40 mmol) were added. The reaction mixture was reacted for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 10f (1.09 g, yield: 76%).

[0680] MS m / z(ESI): 310.2 [M+1].

[0681] Step 6

[0682] (R)-3-(tert-butoxycarbonyl)-9-fluoro-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine 7-oxide 10g

[0683] Compound 10f (450 mg, 1.45 mmol) was dissolved in dichloromethane (10 mL), and hydrogen peroxide (495 mg, 4.37 mmol, 30% by mass) and phthalic anhydride (650 mg, 4.39 mmol) were added under ice bath conditions. The mixture was heated to 35 °C and reacted for 2 hours. The reaction solution was cooled to room temperature, and a saturated sodium thiosulfate solution (30 mL) was added. The mixture was extracted with dichloromethane (10 mL), and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was used directly in the next reaction step.

[0684] MS m / z(ESI): 326.5 [M+1].

[0685] Step 7

[0686] (R)-8-bromo-9-fluoro-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine 10h

[0687] Phosphorus tribromooxy (1.2 g, 4.19 mmol) was added to the filtrate obtained in step 6, and the reaction was allowed to proceed for 30 minutes. A saturated sodium bicarbonate solution (30 mL) was then added to the reaction mixture to obtain a solution of the crude product (title compound 10 h) (416 mg, yield: 96%). This crude product solution was used directly in the next reaction step.

[0688] MS m / z(ESI):288.2[M+1].

[0689] Step 8

[0690] (R)-8-bromo-9-fluoro-1,2,4a,5-tetrahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10i

[0691] Ethyl acetate (50 mL), di-tert-butyl dicarbonate (630 mg, 2.89 mmol), and triethylamine (1.5 g, 14.82 mmol) were added to a solution of the crude product compound 10h (416 mg, 1.44 mmol) from step 7. The reaction mixture was reacted for 1 hour. The reaction solution was extracted with ethyl acetate (30 mL × 3), and the organic phase was separated. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 10i (50 mg, yield: 9%).

[0692] MS m / z(ESI): 388.2 [M+1].

[0693] Step 9

[0694] (R)-8-(2,6-bis(benzyloxy)pyridin-3-yl)-9-fluoro-1,2,4a,5-tetrahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10j

[0695] Compound 10i (50 mg, 0.13 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (55 mg, 0.13 mmol) were dissolved in 5 mL of a mixed solvent of 1,4-dioxane and water (V / V = 4:1). 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium chloride (10 mg, 0.02 mmol) and anhydrous potassium carbonate (40 mg, 0.29 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 10j (50 mg, yield: 65%) MS m / z (ESI): 599.3 [M+1].

[0696] Step 10

[0697] (4aR)-8-(2,6-dioxopiperidin-3-yl)-9-fluoro-1,2,4a,5-tetrahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10k

[0698] Compound 10j (50 mg, 0.08 mmol) was dissolved in ethyl acetate (5 mL), and 10% wet palladium on carbon (containing 50% water, 8 mg, 0.004 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 8 mg, 0.03 mmol) were added. The mixture was purged three times with hydrogen, and the temperature was raised to 60 °C for 16 hours under a hydrogen atmosphere. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 10k (35 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0699] MS m / z(ESI):421.4[M+1].

[0700] Step 11

[0701] 3-((R)-9-fluoro-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-8-yl)piperidine-2,6-dione trifluoroacetate 10l

[0702] Compound 10k (85 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 10l (86 mg, yield: 99%). The crude product was used directly in the next step of the reaction without purification.

[0703] MS m / z(ESI): 321.3 [M+1].

[0704] Step Twelve

[0705] 3-((R)-9-fluoro-3-(1-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-8-yl)piperidin-2,6-dione 10

[0706] Compound 10 (86 mg, 0.20 mmol) and compound 7a (50 mg, 0.09 mmol) were dissolved in dimethyl sulfoxide (5 mL), and diisopropylethylamine (70 mg, 0.54 mmol) was added. The reaction was carried out for 10 minutes, followed by the addition of sodium triacetoxyborohydride (60 mg, 0.28 mmol). The mixture was heated to 50 °C and reacted for 16 hours. Sodium triacetoxyborohydride (60 mg, 0.28 mmol) was then added, and the reaction was carried out at 50 °C for 24 hours. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 0.1% ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 50%-95%, flow rate: 30 mL / min) to give title compound 10 (6 mg, yield: 8%).

[0707] MS m / z(ESI): 858.4 [M+1].

[0708] 1 H NMR (500MHz, DMSO-d6): δ12.40(s,1H),10.84(s,1H),8.55(s,1H),7.46(s,1H),7. 37(d,1H),7.22(d,1H),7.04(s,1H),6.93(d,1H),4.39-3.98(m,8H),3.78-3.72(m ,3H),3.68(s,3H),3.10-3.02(m,3H),2.74-2.69(m,5H),2.59-2.56(m,5H),2.49( s,3H),2.39-2.34(m,1H),2.18-2.12(m,1H),2.05-1.75(m,9H),1.69-1.59(m,3H).

[0709] Examples 11-1 and 11-2

[0710] 3-((6aR,8R)-2-fluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6-yl)piperazine-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[2,3-b:1',2'-d][1,4]oxazine-3-yl)piperidine-2,6-dione 11-1

[0711] 3-((6aR,8S)-2-fluoro-8-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[2,3-b:1',2'-d][1,4]oxazin-3-yl)piperidine-2,6-dione 11-2

[0712] first step

[0713] 3-((R)-2-fluoro-8-oxo-6,6a,7,8,9,10-hexahydrodipyrido[2,3-b:1',2'-d][1,4]oxazin-3-yl)piperidine-2,6-dione 11b

[0714] 3-((R)-2-fluoro-6a,7,9,10-tetrahydro-6H-spiro[dipyrido[2,3-b:1',2'-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-3-yl)piperidin-2,6-dione 11a (180 mg, 0.48 mmol, prepared from intermediate 10k in Example 10, with the first-step starting compound 10a replaced by (R)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (prepared by the method disclosed in the intermediate on pages 34-35 of patent application "WO2022238335A1")) was dissolved in concentrated hydrochloric acid (1 mL) and reacted for 6 hours. The pH of the reaction solution was adjusted to 7-8 by adding saturated sodium bicarbonate solution under ice bath conditions. Extraction was performed with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 11b (140 mg, yield: 88%). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 334.3 [M+1].

[0715] Step 2

[0716] 3-((6aR,8R)-2-fluoro-8-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazine-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[2,3-b:1',2'-d][1,4]oxazine-3-yl)piperidine-2,6-dione 11-1

[0717] 3-((6aR,8S)-2-fluoro-8-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[2,3-b:1',2'-d][1,4]oxazin-3-yl)piperidine-2,6-dione 11-2

[0718] Compound 8i (152 mg, 0.12 mmol) and compound 11b (40 mg, 0.09 mmol) were dissolved in dimethyl sulfoxide (5 mL), and diisopropylethylamine (295 mg, 2.28 mmol) and sodium triacetoxyborohydride (145 mg, 0.69 mmol) were added. The mixture was heated to 60 °C and reacted for 16 hours. The reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Ultimate (30 × 250 mm), 5 μm; elution system: 0.1% aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 45%-75%, flow rate: 30 mL / min) to give the title compound (16 mg, yield: 20%) and (4 mg, yield: 5%).

[0719] 11-1 or 11-2: Shorter retention time compound (16 mg, retention time 13.40 min under preparation conditions): MS m / z (ESI): 858.4 [M+1].

[0720] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),10.84(d,1H),8.55(s,1H),7.46(s,1H),7.37(d,1 H),7.26(d,1H),7.04(s,1H),6.92(d,1H),4.37-4.02(m,7H),3.91(d,1H),3.68(s,3H),3. 18(s,3H),3.07(t,1H),2.76-2.65(m,6H),2.64-2.55(m,6H),2.49(s,3H),2.20-2.11(m, 2H),2.04-1.92(m,3H),1.91-1.76(m,4H),1.64(br,2H),1.54-1.49(m,2H),1.14(qd,1H).

[0721] 11-2 or 11-1: Compounds with longer retention times (4 mg, retention time 16.43 min under preparation conditions): MS m / z (ESI): 858.4 [M+1].

[0722] 1H NMR (500MHz, DMSO-d6): δ12.41(s,1H),10.83(s,1H),8.54(s,1H),7.46(s,1H),7.38( d,1H),7.13(d,1H),7.03(s,1H),6.93(d,1H),4.36-3.97(m,8H),3.67(s,3H),3.47(d ,1H),3.19(s,3H),2.89(t,1H),2.68-2.63(m,6H),2.61-2.56(m,5H),2.49(s,3H),2. 23-2.09(m,3H),2.03-1.98(m,2H),1.91-1.56(m,7H),1.36-1.30(m,1H),1.04(d,1H).

[0723] Example 12

[0724] 3-((1'-(1-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)amino)piperidin-2,6-dione 12

[0725] first step

[0726] N-(1'-benzyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)-1,1-diphenylmethyleneimine 12b

[0727] 1'-Benzyl-6-chloro-3H-spiro[benzofuran-2,4'-piperidine]12a (250 mg, 0.79 mmol, prepared using the method disclosed on page 131 of patent application "WO2010144571A1, intermediate I-11"), benzophenone imine (288 mg, 1.59 mmol, Adamas reagent) were dissolved in 4 mL of a mixed solvent of toluene and N,N-dimethylformamide (V / V = 1 / 1). Tris(dibenzylacetone) palladium (73 mg, 0.08 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (93 mg, 0.16 mmol), and sodium tert-butoxide (154 mg, 1.60 mmol) were added. The mixture was purged with nitrogen three times and placed in a microwave reactor, heated to 140 °C, and reacted for 1.5 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 12b (220 mg, yield: 50%). MS m / z (ESI): 459.2 [M+1].

[0728] Step 2

[0729] 1'-Benzyl-3H-spiro[benzofuran-2,4'-piperidine]-6-amine hydrochloride 12c

[0730] Compound 12b (220 mg, 0.48 mmol) was dissolved in methanol (2 mL), and 4 M hydrochloric acid (0.4 mL) was added dropwise under ice bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 12c (176 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0731] MS m / z(ESI):295.1[M+1].

[0732] Step 3

[0733] 3-((1'-benzyl-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)amino)piperidin-2,6-dione 12d

[0734] Compound 12c (176 mg, 0.48 mmol) was dissolved in acetonitrile (5 mL), and 3-bromopiperidin-2,6-dione (276 mg, 1.44 mmol) and sodium bicarbonate (202 mg, 2.40 mmol) were added. The mixture was heated to 90 °C and reacted for 16 hours. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 12d (90 mg, yield: 46%).

[0735] MS m / z(ESI): 406.2 [M+1].

[0736] Step 4

[0737] 3-((3H-spiro[benzofuran-2,4'-piperidine]-6-yl)amino)piperidine-2,6-dione 12e

[0738] Compound 12d (90 mg, 0.22 mmol) was dissolved in methanol (5 mL), and 10% wet palladium on carbon (containing 50% water, 25 mg, 0.012 mmol) was added. The mixture was purged three times with hydrogen and reacted under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 12e (50 mg, yield: 71%). The crude product was used directly in the next reaction without purification.

[0739] MS m / z(ESI): 316.1 [M+1].

[0740] Step 5

[0741] 3-((1'-(1-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 --yl)piperidine

[0742] -4-yl)-3H-spiro[benzofuran-2,4'-piperidine]-6-yl)amino)piperidine-2,6-dione 12

[0743] Compound 7a (32 mg, 0.06 mmol) and compound 12e (32 mg, 0.09 mmol) were dissolved in 1,2-dichloroethane (4 mL), and diisopropylethylamine (45 mg, 0.35 mmol) and sodium triacetoxyborohydride (50 mg, 0.24 mmol) were added. The mixture was heated to 50 °C and reacted for 16 hours. Sodium triacetoxyborohydride (18 mg, 0.08 mmol) was added, and the mixture was reacted at 50 °C for 2 hours. Sodium triacetoxyborohydride (18 mg, 0.08 mmol) was added again, and the mixture was reacted at 50 °C for 4 hours. The reaction mixture was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-75%, flow rate: 30 mL / min) to give title compound 12 (6 mg, yield: 12%).

[0744] MS m / z(ESI): 853.4 [M+1].

[0745] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),10.78(s,1H),8.54(s,1H),7.46(s,1H),7.37(d,1H),7.03(s, 1H),6.93(d,1H),6.86(d,1H),6.20-6.14(m,2H),5.67(d,1H),4.40-4.03(m,6H),3.75(t,2H),3.68(s ,3H),2.83(s,2H),2.79-2.64(m,6H),2.62-2.56(m,6H),2.49(s,4H),2.13-2.08(m,1H),2.03-1.97( m,2H),1.92-1.80(m,6H),1.76-1.69(m,2H),1.67-1.60(m,2H),1.50-1.43(m,1H),1.35-1.28(m,2H).

[0746] Example 13

[0747] 3-((1'-(1-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidine-4-yl)-3H-spiro[benzofuran-2,4'-piperidine]-5-yl)amino)piperidine-2,6-dione 13

[0748] first step

[0749] 3-Hydroxy-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13b

[0750] 1.5 g (4.94 mmol, Leyan reagent) of tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid 13a was dissolved in 12 mL of a mixture of tetrahydrofuran and methanol (V / V = 1 / 1). Sodium borohydride (374 mg, 9.89 mmol) was added in portions under ice-water bath cooling, and the reaction was maintained under ice bath conditions for 1 hour. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 13b (1.35 g, yield: 89%). The crude product was used directly in the next reaction without purification.

[0751] MS m / z(ESI): 304.2 [M-1].

[0752] Step 2

[0753] 3H-spiro[benzofuran-2,4'-piperidine]trifluoroacetate 13c

[0754] Compound 13b (1.35 g, 4.42 mmol) was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.1 g, 9.46 mmol) was slowly added. The mixture was heated to 50 °C and reacted for 3 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 13c (1.35 g, yield: 99%). The crude product was used directly in the next reaction without purification.

[0755] MS m / z(ESI):190[M+1].

[0756] Step 3

[0757] 3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13d

[0758] Compound 13c (1.35 g, 4.45 mmol) was dissolved in dichloromethane (30 mL), and water (15 mL), sodium bicarbonate (1.87 g, 22.26 mmol), and di-tert-butyl dicarbonate (1.95 g, 8.93 mmol) were added. The reaction mixture was reacted for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 13d (1.01 g, yield: 78%). MS m / z (ESI): 190.2 [M-99].

[0759] Step 4

[0760] 5-Bromo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13e

[0761] Compound 13d (1.01 g, 3.49 mmol) was dissolved in 8 mL of a mixed solvent of methanol and tetrahydrofuran (V / V = 1 / 1), and N-bromosuccinimide (622 mg, 3.49 mmol) was added. The reaction mixture was reacted for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 13e (1.06 g, yield: 82%).

[0762] MS m / z(ESI):268.0[M-99].

[0763] Step 5

[0764] 5-((diphenylmethyl)amino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13f

[0765] Compound 13e (215 mg, 0.58 mmol) and benzophenone imine (148 mg, 0.82 mmol) were dissolved in toluene (10 mL). Sodium tert-butoxide (85 mg, 0.88 mmol), tris(2,2'-benzylacetone) palladium (27 mg, 0.03 mmol), and S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (36 mg, 0.06 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 13f (257 mg, yield: 94%).

[0766] MS m / z(ESI):469.2[M+1].

[0767] Step 6

[0768] 13g of 5-amino-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester

[0769] Compound 13f (217 mg, 0.46 mmol) was dissolved in methanol (15 mL), and hydroxylamine solution (300 mg, 4.54 mmol, 50% by mass) was added. The reaction mixture was reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 13 g (140 mg, yield: 99%).

[0770] MS m / z(ESI): 305.3 [M+1].

[0771] Step 7

[0772] 5-((2,6-dioxopiperidin-3-yl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-carboxylic acid tert-butyl ester 13h

[0773] 13 g (64 mg, 0.21 mmol) of compound 13 g and 3-bromopiperidin-2,6-dione (123 mg, 0.64 mmol) were added to a 15 mL sealed tube, followed by sodium bicarbonate (89 mg, 1.06 mmol) and acetonitrile (3 mL). The mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the crude title compound 13 h (86 mg, yield: 99%).

[0774] MS m / z(ESI): 416.2 [M+1].

[0775] Step 8

[0776] 3-((3H-spiro[benzofuran-2,4'-piperidin]-5-yl)amino)piperidin-2,6-dione trifluoroacetate 13i

[0777] Compound 13h (13 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The reaction mixture was allowed to react for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 13i (34 mg, yield: 100%). The crude product was used directly in the next reaction without purification.

[0778] MS m / z(ESI): 316.2 [M+1].

[0779] Step 9

[0780] 3-((1'-(1-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidine-4-yl)-3H-spiro[benzofuran-2,4'-piperidine]-5-yl)amino)piperidine-2,6-dione 13

[0781] Compound 7a (20 mg, 0.04 mmol) and compound 13i (34 mg, 0.034 mmol) were dissolved in dimethyl sulfoxide (2.5 mL), and diisopropylethylamine (45 mg, 0.35 mmol) and sodium triacetoxyborohydride (23 mg, 0.11 mmol) were added. The mixture was heated to 50 °C and reacted for 6 hours. Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added, and the reaction was continued at 50 °C for 16 hours. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-70%, flow rate: 30 mL / min) to give title compound 13 (6 mg, yield: 21%).

[0782] MS m / z(ESI): 853.6 [M+1].

[0783] 1H NMR(500MHz,DMSO-d6):12.37(s,1H),10.76(s,1H),8.54(s,1H),7.46(s,1H),7.36(d,1H),7.03(d,1 H),6.93(dd,1H),6.60(d,1H),6.51(d,1H),6.43(dd,1H),5.29(d,1H),4.31(br,1H),4.22-4.13(m,3 H),4.03(br,1H),3.75(t,2H),3.68(s,3H),2.89(s,2H),2.76-2.68(m,4H),2.61-2.55(m,6H),2.48( s,3H),2.13-2.10(m,1H),2.03-1.97(m,4H),1.92-1.76(m,7H),1.75-1.55(m,6H),1.49-1.45(m,2H).

[0784] Example 14

[0785] 3-((1'-(1-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)piperidin-2,6-dione 14

[0786] first step

[0787] 6-((2,6-dioxopiperidin-3-yl)amino)-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 14b

[0788] 6-Amino-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 14a (275 mg, 0.90 mmol, prepared according to the method disclosed in step A to step D of compounds 11 and 12 on page 121 of patent application WO2024015346A1) and 3-bromopiperidine-2,6-dione (450 mg, 2.34 mmol) were added to a 100 mL sealed tube, along with sodium bicarbonate (380 mg, 4.52 mmol) and acetonitrile (12 mL). The mixture was heated to 85 °C and reacted for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 14b (70 mg, yield: 19%).

[0789] MS m / z(ESI):416.4[M+1].

[0790] Step 2

[0791] 3-((2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)piperidin-2,6-dione trifluoroacetate 14c

[0792] Compound 14b (30 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The reaction mixture was allowed to react for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 14c (63 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0793] MS m / z(ESI): 316.2 [M+1].

[0794] Step 3

[0795] 3-((1'-(1-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)piperidin-2,6-dione 14

[0796] Compound 7a (30 mg, 0.05 mmol) and compound 14c (63 mg, 0.07 mmol) were dissolved in dimethyl sulfoxide (2.5 mL), and diisopropylethylamine (70 mg, 0.54 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) were added. The mixture was heated to 50 °C and reacted for 16 hours. Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was then added, and the reaction was continued at 50 °C for 4 hours. The reaction mixture was filtered and purified by preparative high-performance liquid chromatography (SHIMADZU LC, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-70%, flow rate: 30 mL / min) to give title compound 14 (10 mg, yield: 21%).

[0797] MS m / z(ESI): 853.6 [M+1].

[0798] 1 H NMR (500MHz, DMSO-d6): δ12.40(s,1H),10.78(s,1H),8.54(s,1H),7.46(s,1H),7.36(d,1H),7. 02(s,1H),6.92-6.89(m,2H),6.19(dd,1H),6.14(d,1H),5.74(d,1H),4.36-4.02(m,7H),3.73(t ,2H),3.67(s,3H),2.87(d,2H),2.78-2.65(m,3H),2.60-2.55(m,6H),2.49(s,3H),2.40-2.36( m,1H),2.20(t,2H),2.12-2.07(m,1H),2.03-1.97(m,1H),1.92-1.75(m,9H),1.64-1.58(m,5H).

[0799] Example 15

[0800] 3-(4,6-difluoro-1'-(1-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclopentacyclononafen-5 6-yl)piperidin-4-yl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-2,6-dione 15

[0801] first step

[0802] 1-Benzyl-4-(2,4,6-trifluorobenzyl)piperidin-4-ol 15b

[0803] Magnesium powder (540 mg, 22.21 mmol) and diethyl ether (12 mL) were placed in a three-necked flask equipped with a reflux tube. Iodine (11 mg, 0.04 mmol) was added, and the mixture was heated to 40 °C. An ether solution (8 mL) of 2-(bromomethyl)-1,3,5-trifluorobenzene 15a (1 g, 4.44 mmol, Adamas reagent) was slowly added dropwise while maintaining reflux. Reflux was continued for 1 hour after the addition was complete. After the reaction solution cooled to room temperature, it was added dropwise at -65 °C to an ether solution (10 mL) of N-benzylpiperidinone (757 mg, 3.99 mmol, Bioderm Pharmaceuticals). After the addition was complete, the mixture was allowed to naturally warm to room temperature and reacted for 16 hours. Under ice bath conditions, a saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 15b (320 mg, yield: 24%).

[0804] MS m / z(ESI): 336.1 [M+1].

[0805] Step 2

[0806] 1'-Benzyl-4,6-difluoro-3H-spiro[benzofuran-2,4'-piperidine]15c

[0807] Compound 15b (320 mg, 0.95 mmol) was dissolved in 12 mL of a mixed solvent of toluene and N,N-dimethylformamide (V / V = 6 / 1). Sodium hydride (183 mg, 4.77 mmol, 60% purity) was added under ice bath conditions, and the mixture was heated to 110 °C for 4 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added to the reaction solution under ice bath conditions. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated sodium chloride solution (30 mL × 2). The solution was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 15c (300 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0808] MS m / z(ESI): 316.1 [M+1].

[0809] Step 3

[0810] 4,6-Difluoro-3H-spiro[benzofuran-2,4'-piperidine]15d

[0811] Compound 15c (220 mg, 0.70 mmol) was dissolved in methanol (5 mL), and 10% wet palladium on carbon (containing 50% water, 15 mg) was added. The mixture was purged three times with hydrogen, and the reaction was carried out at 45 °C for 5 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 15d (150 mg, yield: 95%). The crude product was used directly in the next reaction without purification.

[0812] MS m / z(ESI):226.1[M+1].

[0813] Step 4

[0814] 5-Bromo-4,6-difluoro-3H-spiro[benzofuran-2,4'-piperidine]15e

[0815] Compound 15d (150 mg, 0.66 mmol) was dissolved in methanol (5 mL), and N-bromosuccinimide (261 mg, 1.46 mmol) was added under ice bath conditions. The reaction mixture was reacted under ice bath conditions for 16 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 15e (202 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0816] MS m / z(ESI):304.0[M+1].

[0817] Step 5

[0818] 5-Bromo-4,6-difluoro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester 15f

[0819] Compound 15e (95 mg, 0.31 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (64 mg, 0.63 mmol) and di-tert-butyl dicarbonate (82 mg, 0.38 mmol) were added. The reaction mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 15f (120 mg, yield: 95%).

[0820] MS m / z(ESI):348.1[M-55].

[0821] Step 6

[0822] 15g of 5-(2,6-bis(benzyloxy)pyridin-3-yl)-4,6-difluoro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester

[0823] Compound 15f (120 mg, 0.30 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (174 mg, 0.42 mmol) were dissolved in 4.8 mL of a mixed solvent of 1,4-dioxane and water (V / V = 5 / 1), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (20 mg, 0.03 mmol) and anhydrous potassium carbonate (83 mg, 0.60 mmol) were added. The mixture was heated to 100 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give 15 g (146 mg, yield: 80%) of the title compound. MS m / z (ESI): 615.2 [M+1].

[0824] Step 7

[0825] 5-(2,6-dioxopiperidin-3-yl)-4,6-difluoro-3H-spiro[benzofuran-2,4'-piperidin]-1'-carboxylic acid tert-butyl ester 15h

[0826] 15 g (146 mg, 0.24 mmol) of the compound was dissolved in 8 mL of a mixed solvent of ethyl acetate and tetrahydrofuran (V / V = 5 / 3). 10% wet palladium on carbon (containing 50% water, 13 mg, 0.01 mmol) and 20% wet palladium hydroxide on carbon (containing 50% water, 17 mg, 0.01 mmol) were added. The mixture was purged three times with hydrogen, and the temperature was raised to 60 °C for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 15h (103 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0827] MS m / z(ESI): 435.2 [M-1].

[0828] Step 8

[0829] 3-(4,6-difluoro-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-2,6-dione trifluoroacetate 15i

[0830] Compound 15h (103 mg, 0.24 mmol) was weighed into a 25 mL single-necked flask, 2 mL of dichloromethane was added, and 0.3 mL of trifluoroacetic acid was added dropwise. The reaction mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 15i (106 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0831] MS m / z(ESI):337.1[M+1].

[0832] Step 9

[0833] 3-(4,6-difluoro-1'-(1-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperidin-4-yl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl)piperidin-2,6-dione 15

[0834] Compound 7a (120 mg, 0.17 mmol) and compound 15i (106 mg, 0.23 mmol) were dissolved in dimethyl sulfoxide (4 mL), and diisopropylethylamine (180 mg, 1.39 mmol) and sodium triacetoxyborohydride (146 mg, 0.69 mmol) were added. The mixture was heated to 50 °C and reacted for 3 hours. Sodium triacetoxyborohydride (73 mg, 0.34 mmol) was added, and the reaction was continued at 50 °C for 3 hours. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2555, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 50%-70%, flow rate: 30 mL / min) to give title compound 15 (70 mg, yield: 46%).

[0835] MS m / z(ESI): 873.4 [M+1].

[0836] 1H NMR (500MHz, DMSO-d6): δ12.42(s,1H),10.91(s,1H),8.54(s,1H),7.46(s,1H),7.36(d,1H) ,7.02(s,1H),6.92(d,1H),6.64(d,1H),4.30-4.03(m,5H),3.74(t,2H),3.67(s,3H),3.46- 3.41(m,1H),3.06-3.00(m,2H),2.84-2.77(m,1H),2.72-2.67(m,4H),2.64-2.56(m,8H),2. 48-2.43(m,4H),2.14-2.06(m,1H),2.03-1.96(m,2H),1.88-1.81(m,9H),1.66-1.58(m,3H).

[0837] Examples 16-1 and 16-2

[0838] 3-((2S,4's)-4,6-difluoro-4'-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -y)piperazine-1-yl)-3H-spiro[benzofuran-2,1'-cyclohexane]-5-yl)piperidine-2,6-dione 16-1

[0839] 3-((2R,4'r)-4,6-difluoro-4'-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6-y)piperazin-1-yl)-3H-spiro[benzofuran-2,1'-cyclohexane]-5-yl)piperidin-2,6-dione 16-2

[0840] first step

[0841] 3-(4,6-difluoro-4'-oxo-3H-spiro[benzofuran-2,1'-cyclohexane]-5-yl)piperidin-2,6-dione 16b

[0842] 3-(4,6-difluoro-3H-dispiro[benzofuran-2,1'-cyclohexane-4',2”-[1,3]dioxapentane]-5-yl)piperidin-2,6-dione 16a (135 mg, 0.34 mmol, prepared from intermediate in Example 15 for 15 h) was dissolved in 2 mL of concentrated hydrochloric acid and reacted for 3 h. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 16b (132 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0843] MS m / z(ESI): 350.1 [M+1].

[0844] Step 2

[0845] 3-((2S,4's)-4,6-difluoro-4'-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazine-1-yl)-3H-spiro[benzofuran-2,1'-cyclohexane]-5-yl)piperidine-2,6-dione 16-1

[0846] 3-((2R,4'r)-4,6-difluoro-4'-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 -dihydro-1 1 H,51 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(1,3)-cyclopentacyclononafen-5 6 -yl)piperazine-1-yl)-3H-spiro[benzofuran-2,1'-cyclohexane]-5-yl)piperidine-2,6-dione 16-2

[0847] Compound 16b (60 mg, 0.15 mmol) and compound 8i (200 mg, 0.16 mmol) were dissolved in dimethyl sulfoxide (3 mL), and diisopropylethylamine (300 mg, 2.32 mmol) was added. The reaction was carried out for 10 min, followed by the addition of sodium triacetoxyborohydride (120 mg, 0.57 mmol), and the mixture was heated to 50 °C and reacted for 16 h. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Ultimate (30 × 250 mm), 5 μm; elution system: 0.1% aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 55%-95%, flow rate: 30 mL / min) to give the title compound (20 mg, yield: 15%) and (15 mg, yield: 11%).

[0848] 16-1 or 16-2: Shorter retention time compound (20 mg, retention time 19.47 min under preparation conditions): MS m / z (ESI): 874.4 [M+1].

[0849] 1 H NMR (500MHz, DMSO-d6): δ12.43(s,1H),10.91(s,1H),8.55(s,1H),7.46(s, 1H),7.38(d,1H),7.03(s,1H),6.92(d,1H),6.65(d,1H),4.31-4.03(m,5H) ,3.68(s,3H),3.18(s,4H),3.00(s,2H),2.85-2.78(m,2H),2.75-2.64(m,5 H),2.56(s,4H),2.49-2.37(m,5H),2.14-1.94(m,5H),1.88-1.58(m,10H).

[0850] 16-2 or 16-1: Compounds with longer retention times (15 mg, retention time 20.12 min under preparation conditions): MS m / z (ESI): 874.4 [M+1].

[0851] 1H NMR (500MHz, DMSO-d6): δ12.39(s,1H),10.91(s,1H),8.55(s,1H),7.46(s,1H),7 .38(d,1H),7.03(s,1H),6.92(d,1H),6.60(d,1H),4.31-4.03(m,5H),3.68(s,3H) ,3.17(s,4H),3.10(s,2H),2.85-2.77(m,2H),2.69(s,4H),2.56(s,5H),2.49(s, 3H),2.44-2.37(m,2H),2.14-2.07(m,1H),2.02-1.66(m,12H),1.57-1.49(m,2H).

[0852] Examples 17-1 and 17-2

[0853] 3-((6aR,8R)-2,4-difluoro-8-(4-((7 2 7 5 -cis)-(E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-1

[0854] 3-((6aR,8S)-2,4-difluoro-8-(4-((7 2 7 5 -cis)-(E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-2

[0855] first step

[0856] ((2,5-cis)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)methanol17b

[0857] Cis-2,5-bis(hydroxymethyl)-tetrahydrofuran 17a (3.14 g, 23.76 mmol, Bio-Tech Pharmaceuticals) and imidazole (3.66 g, 53.76 mmol) were dissolved in dichloromethane (40 mL), purged three times with nitrogen, and tert-butyldiphenylchlorosilane (7.84 g, 28.52 mmol) was added dropwise. The reaction mixture was allowed to react for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 17b (3.12 g, yield: 35%).

[0858] MS m / z(ESI):388.3[M+18].

[0859] Step 2

[0860] 2-(((2,5-cis)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)methyl)isoindoline-1,3-dione 17c

[0861] Compound 17b (3.12 g, 8.42 mmol), phthalimide (2 g, 13.59 mmol), and triphenylphosphine (3.53 g, 13.46 mmol) were dissolved in tetrahydrofuran (40 mL), purged three times with nitrogen, and diisopropyl azodicarbonate (2.73 g, 13.50 mmol) was added dropwise under ice bath cooling. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 17c (3.84 g, yield: 91%).

[0862] MS m / z(ESI): 517.2 [M+18].

[0863] Step 3

[0864] ((2,5-cis)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)methylamine 17d

[0865] Compound 17c (3.84 g, 7.69 mmol) was dissolved in ethanol (30 mL), and 85% hydrazine hydrate (6.79 g, 115.29 mmol) was added. The mixture was heated to 70 °C and reacted for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution (80 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with a saturated sodium bicarbonate solution (40 mL) and a saturated sodium chloride solution (30 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 17d (2.53 g, yield: 89%). The crude product was used directly in the next reaction without purification.

[0866] MS m / z(ESI): 370.2 [M+1].

[0867] Step 4

[0868] ((2,5-cis)-5-(((5-bromo-2-nitrophenyl)amino)methyl)tetrahydrofuran-2-yl)methanol17e

[0869] Compound 17d (2.53 g, 6.85 mmol) and 2-fluoro-4-bromonitrobenzene (1.66 g, 7.55 mmol, Bio-Pharmaceutical) were dissolved in dimethyl sulfoxide (30 mL), and N,N-diisopropylethylamine (4.43 g, 34.28 mmol) was added. The mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, and saturated ammonium chloride solution (60 mL) was added. The mixture was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17e (2.18 g, yield: 96%).

[0870] MS m / z(ESI):331.0[M+1].

[0871] Step 5

[0872] 17g of methyl 2-(5-(((2,5-cis)-5-(((5-bromo-2-nitrophenyl)amino)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid

[0873] Compound 17e (152 mg, 0.46 mmol) and methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid ester 17f (157 mg, 0.60 mmol, prepared by the method disclosed on page 123, intermediate 39, of patent application WO2024246838A1) were dissolved in toluene (6 mL). Cyanomethylene tri-n-butylphosphine (343 mg, 1.42 mmol) was added, the mixture was purged with nitrogen three times, and the temperature was raised to 120 °C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 17 g (272 mg, yield: 99%).

[0874] MS m / z(ESI): 572.1 [M-1].

[0875] Step 6

[0876] 2-(5-(((2,5-cis)-5-(((2-amino-5-bromophenyl)amino)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17h

[0877] 17 g (359 mg, 0.62 mmol) of compound was dissolved in N,N-dimethylformamide (5 mL), and tetrahydroxydiboron (168 mg, 1.87 mmol) was added. Under ice bath cooling, a solution of 4,4'-bipyridine (10 mg, 0.06 mmol) in N,N-dimethylformamide (1 mL) was added dropwise, and the reaction was allowed to proceed for 30 minutes. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 17h (339 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0878] MS m / z(ESI): 544.1 [M+1].

[0879] Step 7

[0880] 2-(5-(((2,5-cis)-5-((6-bromo-2-aminoethylene-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17i

[0881] Compound 17i (339 mg, 0.62 mmol) was dissolved in methanol (6 mL), and cyanogen bromide (200 mg, 1.89 mmol) was added. The reaction mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution (10 mL) was added to the residue. The residue was extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (15 mL × 2). The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17i (229 mg, yield: 64%). MS m / z (ESI): 569.2 [M+1].

[0882] Step 8

[0883] (7 2 7 5 -cis)-(E)-5 6 -bromo-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaza-1(4,5)-pyrazaza-7(2,5)-furanhexacyclic nonafen-3-one 17j

[0884] Compound 17i (229 mg, 0.40 mmol) was dissolved in tetrahydrofuran (10 mL), and bis(trimethylsilyl)aminolithium (0.81 mL, 0.81 mmol, 1 M tetrahydrofuran solution) was added. The reaction mixture was reacted for 2 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17j (154 mg, yield: 71%). MS m / z (ESI): 537.1 [M+1].

[0885] Step 9

[0886] 4-((7 2 7 5 -cis)-(E)-1 1 ,1 3 ,2 6-trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 17kJ of 1-(2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0887] Compound 17j (50 mg, 0.09 mmol) was dissolved in N,N-dimethylacetamide (4 mL), and tert-butyl piperazine-1-carboxylate (52 mg, 0.28 mmol), tris(dibenzylacetone)dipalladium (9 mg, 0.01 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (9 mg, 0.02 mmol) and sodium tert-butoxide (27 mg, 0.28 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17k (58 mg, yield: 97%).

[0888] MS m / z(ESI): 643.3 [M+1].

[0889] Step 10

[0890] (7 2 7 5 -cis)-(E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(piperazine-1-yl)-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaza-1(4,5)-pyrazaza-7(2,5)-furan-hexacyclic nonafen-3-one trifluoroacetate 17l

[0891] Compound 17k (58 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The reaction mixture was allowed to react for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 17l (106 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0892] MS m / z(ESI): 543.3 [M+1].

[0893] Step 11

[0894] 3-((6aR,8R)-2,4-difluoro-8-(4-((7 2 7 5 -cis)-(E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-1

[0895] 3-((6aR,8S)-2,4-difluoro-8-(4-((7 2 7 5 -cis)-(E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6-yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-2

[0896] Compound 17l (106 mg, 0.09 mmol) and compound 8h (32 mg, 0.09 mmol) were dissolved in 1,2-dichloroethane (4 mL), and sodium triacetoxyborohydride (58 mg, 0.27 mmol) and N,N-diisopropylethylamine (117 mg, 0.90 mmol) were added. The mixture was heated to 40 °C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Ultimate C18 (30 × 150 mm), 5 μm; elution system: 0.1% aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 35%-70%, flow rate: 30 mL / min) to give the title compound (8.5 mg, yield: 11%) and (8.4 mg, yield: 11%).

[0897] 17-1 or 17-2: Shorter retention time compound (8.5 mg, retention time 15.00 min under preparation conditions): MS m / z (ESI): 877.3 [M+1].

[0898] 1 H NMR (500MHz, DMSO-d6): δ12.27(s,1H),10.87(s,1H),8.85(s,1H),7.43(s,1H),7.33(d ,1H),7.12(s,1H),6.87(d,1H),6.71(d,1H),4.62(t,1H),4.33-4.13(m,4H),4.10-3.83 (m,5H),3.67(s,3H),3.26-3.03(m,4H),2.84-2.53(m,12H),2.43-2.38(m,1H),2.30-2 .19(m,2H),2.16-2.06(m,2H),2.03-1.87(m,5H),1.83-1.79(m,1H),1.52-1.39(m,2H).

[0899] 17-2 or 17-1: Compounds with longer retention times (8.4 mg, retention time 19.30 min under preparation conditions): MS m / z (ESI): 877.4 [M+1].

[0900] 1H NMR (500MHz, DMSO-d6): δ12.23(s,1H),10.86(s,1H),8.85(s,1H),7.43(s,1H),7.34(d,1H ),7.11(s,1H),6.88(d,1H),6.59(d,1H),4.62(t,1H),4.34-4.12(m,5H),4.07-4.01(m,2H ),3.95-3.88(m,2H),3.66(s,3H),3.23-3.10(m,4H),2.89(t,1H),2.83-2.73(m,2H),2.66 -2.54(m,10H),2.29-2.06(m,5H),2.04-1.89(m,4H),1.82-1.78(m,1H),1.53-1.40(m,2H).

[0901] Examples 17-1-1, 17-2-1

[0902] (R)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 2 S,7 5 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-1-1

[0903] (R)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 2 S,7 5 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5-hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-2-1

[0904] first step

[0905] ((2R,5S)-5-(((5-bromo-2-nitrophenyl)amino)methyl)tetrahydrofuran-2-yl)methanol17e-1

[0906] ((2S,5R)-5-(((5-bromo-2-nitrophenyl)amino)methyl)tetrahydrofuran-2-yl)methanol17e-2

[0907] Resolution: Compound 17e (2.18 g) was chirally resolved (separation conditions: Gilson-281 Prep system, column: (S,S)-Whelk-O1 (20×250 mM, Regis Technologies), 10 μm, mobile phase: n-hexane / ethanol (containing 0.5% 7M NH3 in MeOH) solution = 90 / 10 (v / v)), flow rate 20 mL / min) to give 17e-1 (957 mg) and 17e-2 (702 mg).

[0908] 17e-2: A single configuration compound with a short retention time (18.79 minutes).

[0909] MS m / z(ESI):331.1[M+1].

[0910] Chiral HPLC analysis method: retention time 18.79 min (Agilent 1290DAD, column: ReGIS(S,S)-Whelk-O1 (4.6×150mM), 5 μm; mobile phase: n-hexane / isopropanol (containing 0.1% diethylamine) = 95 / 5 (v / v), flow rate 1 mL / min);

[0911] 17e-1: A single-configuration compound with a relatively long retention time (23.25 minutes).

[0912] MS m / z(ESI):331.1[M+1].

[0913] Chiral HPLC analysis method: retention time 23.25 min (Agilent 1290DAD, column: ReGIS(S,S)-Whelk-O1 (4.6×150mM), 5 μm; mobile phase: n-hexane / isopropanol (containing 0.1% diethylamine) = 95 / 5 (v / v), flow rate 1 mL / min);

[0914] Step 2

[0915] 2-(5-(((2R,5S)-5-(((5-bromo-2-nitrophenyl)amino)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17g-1

[0916] Compound 17e-1 (600 mg, 1.81 mmol) and compound 17f (474 ​​mg, 1.81 mmol) were dissolved in 24 mL of toluene, and cyanomethylenetri-n-butylphosphine (1 g, 4.14 mmol) was added. The mixture was purged with nitrogen three times and heated to 120 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 17g-1 (1.04 g, yield: 99%).

[0917] MS m / z(ESI): 574.1 [M+1].

[0918] Step 3

[0919] 2-(5-(((2R,5S)-5-(((2-amino-5-bromophenyl)amino)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17h-1

[0920] Compound 17 g-1 (1.04 g, 1.81 mmol) and 4,4'-bipyridine (29 mg, 0.18 mmol) were dissolved in 10 mL of N,N-dimethylformamide. Tetrahydroxydiboron (491 mg, 5.48 mmol) was slowly added under ice bath cooling, and the reaction was allowed to proceed for 30 min. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 17 h-1 (993 mg, yield: 99%). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 544.1 [M+1].

[0921] Step 4

[0922] 2-(5-(((2R,5S)-5-((6-bromo-2-aminoethylene-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17i-1

[0923] Compound 17h-1 (993 mg, 1.81 mmol) was dissolved in 30 mL of methanol, and cyanogen bromide (590 mg, 5.57 mmol) was added. The reaction mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue. The residue was washed successively with saturated sodium bicarbonate solution (20 mL × 2) and saturated sodium chloride solution (20 mL × 1). The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17i-1 (704 mg, yield: 67%).

[0924] MS m / z(ESI): 569.2 [M+1].

[0925] Step 5 (7) 2 S,7 5 R,E)-5 6 -bromo-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaza-1(4,5)-pyrazaza-7(2,5)-furan-hexacyclononadenosine-3-one 17j-1

[0926] Compound 17i-1 (704 mg, 1.24 mmol) was dissolved in 40 mL of tetrahydrofuran, and bis(trimethylsilyl)aminolithium (2.47 mL, 2.47 mmol, 1 M in THF) was added. The reaction mixture was reacted for 2 hours. 40 mL of saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17j-1 (477 mg, yield: 72%).

[0927] MS m / z(ESI): 537.1 [M+1].

[0928] Step 6

[0929] 4-((7 2 S,7 5 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 17kJ / (2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0930] Compound 17j-1 (200 mg, 0.37 mmol) was dissolved in 6 mL of N,N-dimethylacetamide, and piperazine-1-carboxylic acid tert-butyl ester (208 mg, 1.12 mmol), tris(dibenzylacetone)dipalladium (34 mg, 0.04 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (35 mg, 0.08 mmol) and sodium tert-butoxide (108 mg, 1.12 mmol) were added. The mixture was purged with nitrogen three times and the temperature was raised to 100 °C for 16 hours. After the reaction solution was cooled to room temperature, 10 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 17k-1 (232 mg, yield: 97%).

[0931] MS m / z(ESI): 643.3 [M+1].

[0932] Step 7

[0933] (7 2 S,7 5 R,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(piperazine-1-yl)-5 2 5 3 7 2 7 3 7 4 7 5-hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(2,5)-furan-hexacyclononafen-3-one trifluoroacetate 17l-1

[0934] Compound 17k-1 (110 mg, 0.17 mmol) was dissolved in 3 mL of dichloromethane, and 0.4 mL of trifluoroacetic acid was added dropwise. The reaction mixture was allowed to react for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 17l-1 (230 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0935] MS m / z(ESI): 543.2 [M+1].

[0936] Step 8

[0937] (R)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 2 S,7 5 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-1-1

[0938] (R)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 2 S,7 5 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,51 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-2-1

[0939] Compound 17l-1 (230 mg, 0.17 mmol) and compound 8l (67 mg, 0.17 mmol) were dissolved in 8 mL of 1,2-dichloroethane. Sodium triacetoxyborohydride (109 mg, 0.51 mmol) and N,N-diisopropylethylamine (222 mg, 1.72 mmol) were added, and the mixture was heated to 40 °C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Ultimate C18 (30 × 150 mm), 5 μm; elution system: 0.1% aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 35%-70%, flow rate: 30 mL / min) to give title compounds 17-2-1 (19 mg, yield: 13%) and 17-1-1 (10 mg, yield: 7%).

[0940] 17-2-1: Compound with shorter retention time (19 mg, retention time 15.23 min under preparation conditions): MS m / z (ESI): 877.6 [M+1].

[0941] 1 H NMR (500MHz, DMSO-d6): δ12.26(s,1H),10.88(s,1H),8.85(s,1H),7.43(s,1H),7.33(d,1H),7.11(s, 1H),6.87(d,1H),6.70(d,1H),4.62(t,1H),4.32-4.14(m,4H),4.07-4.02(m,2H),3.97-3.91(m,3H), 3.67(s,3H),3.21-3.07(m,5H),2.82-2.61(m,7H),2.60-2.52(m,5H),2.29-2.19(m,2H),2.17-2.05( m,2H),2.03-1.87(m,4H),1.84-1.75(m,1H),1.50-1.44(m,1H),1.32-1.26(m,1H),1.20-1.11(m,1H).

[0942] 17-1-1: Compounds with longer retention times (10 mg, retention time 19.42 min under preparation conditions): MS m / z (ESI): 877.7 [M+1].

[0943] 1 H NMR (500MHz, DMSO-d6): δ12.23(s,1H),10.86(s,1H),8.85(s,1H),7.43(s,1H),7.34(d,1H),7.11(s,1H),6 .88(d,1H),6.59(d,1H),4.62(t,1H),4.32-4.13(m,4H),4.08-3.98(m,2H),3.95-3.85(m,2H),3.66(s,3H), 3.48-3.37(m,3H),3.23-3.10(m,4H),2.89(t,1H),2.81-2.74(m,1H),2.72-2.59(m,5H),2.54(s,3H),2.45- 2.41(m,1H),2.28-2.05(m,6H),2.00-1.91(m,2H),1.84-1.75(m,1H),1.73-1.66(m,1H),1.38-1.27(m,2H).

[0944] Examples 17-1-2, 17-2-2

[0945] (R)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 2 R,7 5 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-1-2

[0946] (R)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 2 R,75 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-2-2

[0947] first step

[0948] 2-(5-(((2S,5R)-5-(((5-bromo-2-nitrophenyl)amino)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17g-2

[0949] Compound 17e-2 (500 mg, 1.51 mmol) and compound 17f (394 mg, 1.51 mmol) were dissolved in 20 mL of toluene, and cyanomethylenetri-n-butylphosphine (0.83 g, 3.44 mmol) was added. The mixture was purged with nitrogen three times and heated to 120 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 17g-2 (867 mg, yield: 99%).

[0950] MS m / z(ESI): 574.1 [M+1].

[0951] Step 2

[0952] 2-(5-(((2S,5R)-5-(((2-amino-5-bromophenyl)amino)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17h-2

[0953] Compound 17g-2 (867 mg, 1.51 mmol) and 4,4'-bipyridine (24 mg, 0.15 mmol) were dissolved in 10 mL of N,N-dimethylformamide. Tetrahydroxydiboron (370 mg, 4.13 mmol) was slowly added under ice bath cooling, and the reaction was allowed to proceed for 30 minutes. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, title compound 17h-2 (823 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0954] MS m / z(ESI): 544.0 [M+1].

[0955] Step 3

[0956] 2-(5-(((2S,5R)-5-((6-bromo-2-aminoethylene-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)tetrahydrofuran-2-yl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 17i-2

[0957] Compound 17h-2 (0.82 g, 1.56 mmol) was dissolved in 30 mL of methanol, and cyanogen bromide (497 mg, 4.69 mmol) was added. The reaction mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue. The residue was washed successively with saturated sodium bicarbonate solution (20 mL × 2) and saturated sodium chloride solution (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17i-2 (665 mg, yield: 75%).

[0958] MS m / z(ESI): 569.0 [M+1].

[0959] Step 4

[0960] (7 2 R,7 5 S,E)-5 6 -bromo-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaza-1(4,5)-pyrazaza-7(2,5)-furan-hexacyclononadenosine-3-one 17j-2

[0961] Compound 17i-2 (665 mg, 1.17 mmol) was dissolved in 40 mL of tetrahydrofuran, and bis(trimethylsilyl)aminolithium (2.34 mL, 2.34 mmol, 1 M in THF) was added. The reaction mixture was reacted for 2 hours. 40 mL of saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 17j-2 (425 mg, yield: 68%).

[0962] MS m / z(ESI): 537.1 [M+1].

[0963] Step 5

[0964] 4-((7 2 R,7 5 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 17k-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0965] Compound 17j-2 (200 mg, 0.37 mmol) was dissolved in 6 mL of N,N-dimethylacetamide, and piperazine-1-carboxylic acid tert-butyl ester (208 mg, 1.12 mmol), tris(dibenzylacetone)dipalladium (34 mg, 0.04 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (35 mg, 0.08 mmol) and sodium tert-butoxide (107 mg, 1.11 mmol) were added. The mixture was purged with nitrogen three times and the temperature was raised to 100 °C for 16 hours. After the reaction solution was cooled to room temperature, 10 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 17k-2 (239 mg, yield: 99%).

[0966] MS m / z(ESI): 643.3 [M+1].

[0967] Step 6

[0968] (7 2 R,7 5 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(piperazine-1-yl)-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridazol-1(4,5)-pyrazol-7(2,5)-furan-hexacyclononafen-3-one trifluoroacetate 17l-2

[0969] Compound 17k-2 (110 mg, 0.17 mmol) was dissolved in 3 mL of dichloromethane, and 0.4 mL of trifluoroacetic acid was added dropwise. The reaction mixture was allowed to react for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 17l-2 (230 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0970] MS m / z(ESI): 543.2 [M+1].

[0971] Step 7

[0972] (R)-3-((6aR,8R)-2,4-difluoro-8-(4-((7 2 R,7 5 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-1-2

[0973] (R)-3-((6aR,8S)-2,4-difluoro-8-(4-((7 2 R,7 5 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 7 2 7 3 7 4 7 5 -hexahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridaz-1(4,5)-pyrazaz-7(2,5)-furan-hexacyclononazo-5 6 -yl)piperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)piperidine-2,6-dione 17-2-2

[0974] Compound 17l-2 (230 mg, 0.17 mmol) and compound 8l (67 mg, 0.17 mmol) were dissolved in 8 mL of 1,2-dichloroethane. Sodium triacetoxyborohydride (109 mg, 0.51 mmol) and N,N-diisopropylethylamine (222 mg, 1.72 mmol) were added, and the mixture was heated to 40 °C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (GILSON-281, column: AX-C18 (30 × 150 mm), 5 μm; elution system: 0.1% aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 30%-65%, flow rate: 30 mL / min) to give the title compound (23 mg, yield: 15%) and (21 mg, yield: 14%).

[0975] 17-1-2 or 17-2-2: Shorter retention time compound (23 mg, retention time 13.89 min under preparation conditions): MS m / z (ESI): 877.3 [M+1].

[0976] 1 H NMR (500MHz, DMSO-d6): δ12.27(s,1H),10.88(s,1H),8.86(s,1H),7.43(s,1H),7.33(d,1H),7.11(s,1 H),6.87(d,1H),6.70(d,1H),4.66-4.59(m,1H),4.34-4.14(m,4H),4.09-4.02(m,2H),3.99-3.86(m,3H ), 3.67 (s, 3H), 3.27-3.08 (m, 5H), 2.82-2.62 (m, 6H), 2.61-2.52 (m, 5H), 2.30-2.19 (m, 2H), 2.17-2.07 (m, 2H), 2.02-1.91 (m, 4H), 1.82-1.75 (m, 1H), 1.55-1.42 (m, 2H), 1.32-1.27 (m, 1H), 1.20-1.12 (m, 1H). 17-2-2 or 17-1-2: Compounds with longer retention times (21 mg, retention time 17.35 min under preparation conditions): MS m / z (ESI): 877.4 [M+1].

[0977] 1H NMR (500MHz, DMSO-d6): δ12.27(s,1H),10.87(s,1H),8.85(s,1H),7.43(s,1H),7.34(d,1H),7.11(s,1H),6.88(d,1 H),6.59(d,1H),4.65-4.60(m,1H),4.31(d,1H),4.25-4.13(m,3H),4.08-3.98(m,2H),3.96-3.85(m,2H),3.66(s,3H ),3.51-3.44(m,2H),3.42-3.37(m,2H),3.23-3.10(m,4H),2.89(t,1H),2.81-2.74(m,1H),2.72-2.59(m,5H),2.54 (s,3H),2.45-2.42(m,1H),2.28-2.05(m,6H),1.98-1.92(m,1H),1.86-1.65(m,2H),1.35(t,1H),1.29-1.25(m,1H).

[0978] Biological evaluation

[0979] Test Example 1: Determination of the degradation activity of the disclosed compounds on total EGFR protein of BaF3 / EGFR L858R-T790M-C797S cells.

[0980] 1. Experimental Materials and Instruments

[0981] BaF3 / EGFR L858R-T790M-C797S (also known as BaF3 / LTC, KC-0122) was purchased from Kangyuan Bochuang.

[0982] RPMI 1640 medium (Mellen, PWL015)

[0983] 0.25% Trypsin-EDTA (1×) (Gibco, 25200-072)

[0984] Penicillin-Streptomycin (Gibco, 15140-122)

[0985] PBS (1×) (Meilun, PWL050)

[0986] FBS (Gibco, 10091148)

[0987] HTRF Human Total EGFR Detection Kit (Revvity, 64NG1PEH)

[0988] T75 Flask (Nest, 708003)

[0989] T25 Flask (Nest, 707003)

[0990] Disposable sample dispensing tank (BIOFIL, LTT052050)

[0991] Dimethyl sulfoxide (Sinopharm, 30072418)

[0992] 384 cell culture plate (white opaque 384-well microplate, sterile and tissue culture treated) (PE, 6007680)

[0993] Countstar cell counting chamber (Countstar, 12-0005-50)

[0994] 96-hole round base plate (untreated) (JET BIOFIL, TCP-002-096)

[0995] Automated cell counter (Countstar, IC1000)

[0996] 2L Ultrasonic Cleaner (Titan, UC-2H)

[0997] Centrifuge (Thermo, 75004524)

[0998] Thermo I160 constant temperature incubator

[0999] Small liquid workstation (Tecan, D300E)

[1000] Automatic sample dispenser (Meixing Gaode, S pippette S2)

[1001] EnVision Multimode Board Reader (PerkinElmer, EnVision 2105)

[1002] 2. Experimental Methods

[1003] 2.1. Plating of suspension cells (Day 1)

[1004] a. Observe the state of cells under a microscope.

[1005] b. Collect cells into a 15 mL centrifuge tube, centrifuge at 400 g for 4 minutes. Resuspend the cells in an appropriate amount of complete culture medium.

[1006] c. Take a resuspended cell suspension and count the cells to ensure that the cell viability is greater than 90%.

[1007] d. Adjust the cell density to the appropriate level using complete culture medium, adding 30 μl per well to a 96-well round-bottom plate (10,000 cells per well). Place the cell culture plate in a 37°C incubator. Add the compound on the same day or the following day.

[1008] 2.2 Adding medicine

[1009] a. The compound was sonicated to clarity at 37°C before use. Prepare diluted 3 mM and intermediate concentrations of the test compound at 7.5 μM.

[1010] b. Add 5 μl of the compound (15 μL DMSO) to the D300E slot of the small liquid workstation for compound loading. Use the 0.1% DMSO-treated well as the negative control well.

[1011] c. Place the cells treated with the compound into a 37°C incubator and incubate for 6 or 16 hours.

[1012] 2.3 Cell lysis and antibody incubation (Day 2)

[1013] a. Remove the cell culture plate from the incubator and add 10 μl of 4× lysis buffer (pre-equilibrated to room temperature) to each well using the S2 autopilot. Place the plate on a shaker and incubate at 800 rpm for 60 minutes at room temperature. After incubation, transfer 16 μl / well of the supernatant to a 384 assay plate and briefly centrifuge at 400g.

[1014] The bT-EGFR kit contains two antibodies, d2 and Eu antibodies (stored frozen at -80°C). Calculate the required amount of antibody, dilute the antibody with detection buffer at a ratio of 1:40, and prepare an equal volume mixture of d2 and Eu antibodies.

[1015] c. Divide the prepared antibody mixture into 384-well plates using an electric separator, 4 μl per well. Seal the plates with sealing film, briefly centrifuge at 400 g using a microplate centrifuge, and incubate overnight at room temperature in the dark.

[1016] 2.4 HTRF Signal Detection (Day 3)

[1017] a. Centrifuge at 400g for 2 minutes, and read the fluorescence values ​​at 665nm and 620nm using an Envision multi-functional microplate reader.

[1018] 2.5, DC 50 Value and maximum degradation rate calculation

[1019] a. Calculate the degradation rate of the compound at each concentration using the following formula, and use XLfit to perform curve fitting based on the logarithmic concentration and degradation rate of the compound, and calculate DC. 50 value.

[1020] b. Degradation rate (%) = 100 - 100 × (HTRF signal ratio) 化合物 -HTRF signal ratio 空白对照 ) / (HTRF signal ratio 溶媒对照 -HTRF signal ratio 空白对照 Blank control: only lysis buffer, no cell group; solvent control: DMSO treated cell group.

[1021] The bioactivity of the compound disclosed herein is obtained from the above analysis, and the calculated DC is... 50 As shown in Tables 1 and 2 below.

[1022] Table 1. Degradation activity of the disclosed compounds against BaF3 / LTC mutant cells after 16 hours.

[1023] Conclusion: The disclosed compound exhibits excellent degradation activity against BaF3 / LTC cells after 16 hours.

[1024] Table 1-2. Degradation activity of the disclosed compounds against BaF3 / LTC mutant cells after 6 hours.

[1025] Conclusion: The disclosed compound exhibits excellent degradation activity against BaF3 / LTC cells after 6 hours.

[1026] Test Example 2: Determination of the inhibitory effect of the disclosed compounds on the proliferation of BaF3 / EGFR L858R-T790M-C797S, BaF3 / EGFR L858R-C797S, BaF3 / EGFR Del19-T790M-C797S, BaF3 / EGFR Del19-T790M, BaF3 / EGFR L858R, H1975 / EGFR L858R-T790M, A431 / EGFR WT, NCI-H292 / EGFRWT, HCC827 / EGFR Del19, PC9 / EGFR Del19-T790M-C797S, PC9 / EGFR Del19-C797S, and H1975 / EGFR L858R-C797S cells.

[1027] 1. Experimental Materials and Instruments

[1028] BaF3 / EGFR L858R-T790M-C797S (also known as BaF3 / LTC, KC-0122), PC9 / EGFR Del19-C797S (also known as PC9 / DC, KC-5630), and H1975 / EGFR L858R-C797S (also known as H1975 / LC, KC-5583) were purchased from Kangyuan Bochuang; BaF3 / EGFR L858R-C797S (also known as BaF3 / LC, CBP73047), BaF3 / EGFR Del19-T790M-C797S (also known as BaF3 / DTC, CBP73173), BaF3 / EGFR Del19-T790M (also known as BaF3 / DT, CBP73046), BaF3 / EGFR L858R (also known as BaF3 / L, CBP73040) and PC9 / EGFR Del19-T790M-C797S (also known as PC9 / DTC, CBP73397) were purchased from Nanjing Kebai; H1975 / EGFR L858R-T790M (also known as H1975 / LT, CRL-5908), A431 / EGFR WT (also known as A431 / WT, CRL-1555), NCI-H292 / EGFR WT (also known as H292 / WT, CRL-1848), and HCC827 / EGFR Del19 (also known as HCC827 / D, CRL-2868) were purchased from ATCC.

[1029] DMEM medium (Corning, 10-013-CV)

[1030] RPMI 1640 medium (Mellen, PWL015)

[1031] Puromycin (10 mg / ml) (ThermoFisher, A11138-03)

[1032] 0.25% Trypsin-EDTA (1×) (Gibco, 25200-072)

[1033] Penicillin-Streptomycin (Gibco, 15140-122)

[1034] DPBS (1×) (Gibco, 14190-144)

[1035] FBS (Gibco, 10091148)

[1036] GlutaMAX(100×)(Gibco, 35050-061)

[1037] T75 Flask (TITAN, 02055020)

[1038] 384 cell culture plate (white opaque 384-well microplate, sterile and tissue culture treated) (PE, 6007480)

[1039] 96-well round-bottom dispensing plate (untreated) (JET BIOFIL, TCP-002-096)

[1040] 1.2mL 96-well deep plate (transparent, sterile, square wells, V-bottom) (TITAN, 02089063)

[1041] CellTiter-Glo buffer (Promega, G756B)

[1042] CellTiter-Glo substrate (Promega, G755B)

[1043] Automated cell counter (Countstar, IC1000)

[1044] Centrifuge (Thermo, 75004524)

[1045] Thermo I160 constant temperature incubator

[1046] EnVision Multimode Board Reader (PerkinElmer, EnVision 2105)

[1047] Small liquid workstation (Tecan, D300E)

[1048] 2. Experimental Methods

[1049] 2.1 Adherent cell plating (Day 0)

[1050] a. Observe the cell state under a microscope to ensure that the cell confluence is ~90%.

[1051] b. Discard the cell supernatant, rinse once with PBS, and discard the PBS. Add an appropriate amount of trypsin to digest the cells, and incubate at 37°C for about 5 minutes.

[1052] c. Stop digestion with an equal volume of 1640 medium containing 10% FBS, and collect the cell suspension. Centrifuge at 300g for 3 minutes. Resuspend the cells in an appropriate amount of fresh medium.

[1053] d. Take 20 μL of the resuspended cell suspension for counting, ensuring that the cell viability is greater than 90%.

[1054] e. Based on the cell count results, dilute the cells to the appropriate seeding density using DMEM (A431 / WT) containing 10% FBS, or RPMI1640 (H1975 / LT, H292 / WT, and HCC827 / D), or RPMI1640 with 2 μg / ml puromycin (PC9 / DTC), or RPMI1640 with 1 μg / ml puromycin (PC9 / DC and H1975 / LC). Seed the cells in 384-well plates at a density of 2000 (A431 / WT), 150 (H1975 / LT and H1975 / LC), 200 (HCC827 / D), or 300 (PC9 / DTC, H292 / WT, and PC9 / DC) cells per well, 40 μL per well.

[1055] f. Incubate the cell culture plate overnight in an incubator at 37°C with 5% carbon dioxide.

[1056] 2.2. Plating of suspended cells (Day 1)

[1057] a. Observe the cell state under a microscope.

[1058] b. Collect the cell suspension into a 15mL centrifuge tube, centrifuge at 400g for 4 minutes. Resuspend the cells in an appropriate amount of fresh culture medium.

[1059] c. Take 20 μL of the resuspended cell suspension for cell counting, ensuring that the cell viability is greater than 90%.

[1060] d. Based on the cell count results, dilute the cells to the appropriate seeding density with RPMI 1640 medium containing 10% FBS, and seed the cells into 384-well culture plates at a density of 400 cells per well (BaF3 / LTC, BaF3 / LC, BaF3 / DTC, BaF3 / DT or BaF3 / L), 40 μL per well.

[1061] 2.3 Administering medication (Day 1)

[1062] a. The initial concentration of the compound is 3 mM. Intermediate point dilution: Dilute the 3 mM working solution of the compound 200-fold with DMSO. Add 2 μL of the 3 mM compound to 398 μL of DMSO, and dilute each compound to 15 μM as an intermediate concentration; use a D300E initiator for separatory dilution. The final result is a 3-fold serial dilution. The concentration ranges of different compounds are determined according to IC50. 50 (Adjustments may be made accordingly depending on the differences)

[1063] b. Place the cell plate after drug administration in an incubator at 37°C with 5% carbon dioxide for incubation.

[1064] 2.4 CTG test (day 4)

[1065] a. Before use, allow the CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate to equilibrate to room temperature, and mix them thoroughly to prepare 100 mL of CellTiter-Glo reagent (or equilibrate the mixed CellTiter-Glo reagent from -20℃ to room temperature).

[1066] b. Remove the plate to be tested from the incubator, allow it to equilibrate to room temperature, and add 20 μL of CellTiter-Glo reagent to each well.

[1067] c. Shake and mix for 2 minutes to allow the cells to fully lyse.

[1068] d. After the signal stabilizes at room temperature for 28 minutes, the emission signal value (RLU) is detected on the EnVision device.

[1069] 2.4, IC 50 Value and maximum inhibition rate calculation

[1070] a. Calculate the inhibition rate of the compound at each concentration using the following formula, and use XLfit to perform curve fitting based on the logarithmic concentration and inhibition rate of the compound, and calculate the IC50. 50 value.

[1071] b. Inhibition rate (%) = 100 - 100 × (RLU) 化合物 -RLU 空白对照 ) / (RLU 溶媒对照 -RLU 空白对照 )

[1072] The bioactivity of the compound disclosed herein is obtained from the above analysis, and the calculated IC50 value is... 50 As shown in Tables 3, 4 and 5 below.

[1073] Table 3. Inhibitory activity of the compounds disclosed herein against the proliferation of HCC827 / D mutant cells.

[1074] Conclusion: The compound disclosed herein has a good inhibitory effect on the proliferation of HCC827 / D mutant cells.

[1075] Table 4. Inhibitory activity of the disclosed compounds against the proliferation of H1975 / LT and PC9 / DTC mutant cells

[1076] Conclusion: The compound disclosed herein has a good inhibitory effect on the proliferation of H1975 / LT and PC9 / DTC mutant cells.

[1077] Note: " / " has not yet been detected.

[1078] Table 5. Inhibitory activity of the disclosed compounds against the proliferation of BaF3 / LTC, BaF3 / DTC, BaF3 / L, BaF3 / DT, H1975 / LC, PC9 / DC, and H292 / WT mutant cells.

[1079] Conclusion: The disclosed compound has a good inhibitory effect on the proliferation of BaF3 / LTC, BaF3 / DTC, BaF3 / L, BaF3 / DT, H1975 / LC and PC9 / DC mutant cells.

[1080] Note: " / " has not yet been detected.

[1081] Test Example 3: Stability and clearance rate of the disclosed compound in liver microsomes

[1082] I. Experimental Materials and Instruments

[1083] 1. Phosphate buffer (20×PBS, purchased from Sangon Biotech)

[1084] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[1085] 3. Human liver microsomal solution (BIOIVT, Lot No.: OUP, protein concentration 20 mg / mL)

[1086] 4. Canine liver microsomal solution (XENOTECH, Lot No.: 2110225, protein concentration 20 mg / mL)

[1087] 5. Mouse liver microsomal solution (TPCS, Lot No.: LMSD-2312V244, protein concentration 20 mg / mL)

[1088] 6. ACQUITY BEH C 18 Column, 2.1×50mm, 1.7μm (Waters Corporation, USA)

[1089] 7. Quality control compound (testosterone, ZZBIO, Lot No.: 25w099-Z5)

[1090] 8. Shimadzu LC-30AD UPLC-API4000 tandem mass spectrometer (AB SCIEX)

[1091] 9. Compare with Example 1: It was synthesized according to the method reported in Example 74 of WO2024246838A1.

[1092] II. Experimental Procedure

[1093] 1. Weighing and preparation of NADPH: Weigh an appropriate amount of NADPH (MW = 833.4 g / mol) powder, add it to PBS buffer to dissolve, mix well to obtain a 5 mM working solution for later use.

[1094] 2. Preparation of test compound solution: Accurately weigh an appropriate amount of the test compound, dissolve it in DMSO to prepare a 30 mM stock solution. Transfer 5 μL of this stock solution to a 1.5 mL Eppendorf tube, add 295 μL of LCN and dilute to 500 μM to obtain working solution I. Transfer 50 μL of working solution I to a 10 mL Eppendorf tube, add 4950 μL of PBS buffer and dilute to a concentration of 5 μM to obtain working solution II.

[1095] 3. Preparation of working solution for liver microsomes: Take an appropriate amount of commercially available liver microsomes (protein concentration of 20 mg / mL) from each species and dilute them with 100 mM phosphate buffer (pH 7.4) to a microsome solution of 0.833 mg / mL for later use.

[1096] 4. Preparation of MgCl2 solution: Weigh an appropriate amount of MgCl2 powder and prepare a 300mM stock solution with deionized water for later use.

[1097] 5. Liver microsomal incubation system and sample preparation

[1098] Accurately transfer 20 μL of the working solution II of the test compound and 60 μL of the 0.833 mg / mL microparticle solution into a 1.2 mL 96-well plate and mix thoroughly. Incubate in a 37°C water bath for 5 min, then remove and add 20 μL of 5 mM NADPH solution to start the reaction. For the negative control sample, add 20 μL of PBS instead of the NADPH solution. Terminate the reaction by adding 250 μL of acetonitrile solution containing an internal standard (100 ng / mL) at 0, 5, 15, 30, and 45 min, respectively. Centrifuge the sample at 3700 rpm for 15 min, transfer 90 μL of the supernatant to 90 μL of distilled water, vortex for 5 min, and then perform LC-MS / MS analysis on 5 μL of the mixture. Quality control samples were prepared using the same method.

[1099] III. Experimental Results

[1100] Table 6. Stability and clearance rate of the compounds disclosed herein in liver microsomes

[1101] Conclusion: The compound disclosed herein is more stable in in vitro microsomal metabolism and has pharmacokinetic advantages.

[1102] Test Example 4: Pharmacokinetic Evaluation

[1103] I. SD Rat Experiment

[1104] 1. Abstract

[1105] Using SD rats as test animals, the plasma drug concentrations of the disclosed compound at different time points after intravenous (iv) and gavage (ig) administration were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated to evaluate its pharmacokinetic characteristics.

[1106] 2. Test Plan

[1107] 2.1 Test Drugs

[1108] This disclosure includes compound 17-2-1 and control example 1.

[1109] 2.2 Experimental Animals

[1110] Sixteen SD rats were randomly divided into four groups, with two females and two males in each group. They were provided by Viton Lever Laboratories. After fasting overnight, the drugs were administered intravenously and by gavage, respectively.

[1111] 2.3 Drug Preparation

[1112] Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a colorless and clear solution of 0.2 mg / mL.

[1113] 2.4 Administration

[1114] The dosage is 2.0 mg / kg, and the administration volume is 10.0 mL / kg.

[1115] 3. Operation

[1116] Intravenous group: Blood samples of 0.1 mL were collected from the orbital cavity before administration and at 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24.0 hours after administration. In the gavage group: Blood samples of 0.1 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 10,000 rpm for 1 minute (4℃), and plasma was separated within 1 hour and stored at -20℃ for analysis. The blood collection and centrifugation processes were performed under ice bath conditions. Patients ate 2 hours after administration.

[1117] The content of the analyte compound in the plasma of SD rats after administration of different drug concentrations was determined: 20 μL of rat plasma samples were taken at each time point after drug administration, and 200 μL of acetonitrile solution containing the internal standard (verapamil (50 ng / mL)) was added. The mixture was vortexed and centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was added to an equal volume of pure water and mixed well. 1 μL of the mixed sample was analyzed by LC / MS / MS. The results are shown in Table 7.

[1118] Table 7. Pharmacokinetic parameters of the compounds disclosed herein in rats.

[1119] Conclusion: The compound disclosed herein has a high exposure level in SD rats and exhibits pharmacokinetic advantages.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof: in: The ring C is selected from heterocyclic, aryl, and heteroaryl groups; Ring D is aryl or heteroaryl; Ring A is selected from * The key is connected to W; Key and L 6 connect; X, Y, and Z may be the same or different, and each is independently selected from bond, O, and S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O); W is selected from bond, O, S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O); V is N or CR 0 ; t1 and t2 are each independently 0, 1, 2 or 3; a1 and a2 are each independently 0, 1, 2, 3, 4 or 5; A 1 For N or CR A1 A 2 For N or CR A2 ; R A1 R A2 and R 0 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl and cycloalkylalkyl; X 1 X 2 and X 3 Whether they are the same or different, and each is independently N or CR X ; X 4 and X 5 Whether they are the same or different, and each is independently N or CR 3 ; R 2 R 3 R 5 and R X The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, deuteralkyl, deuteroxy, hydroxyl, alkenyl, alkynyl, cyano, NR 11 R 12 C(O)NR 11 R 12 alkylene NR 11 R 12 alkylene C(O)NR 11 R 12 OR 14 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v OR 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R 01 Replaced; Or two Rs 3 Together with the carbon atom attached thereto, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups; each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. 01 Replaced; J 1 Selected from bond, O, S(O) v NR J C(O), C(O)NR J NR J C(O), (CR) c R d ) y cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently and optionally composed of one or more R groups. 02 Replaced; J 2 J 3 J 4 J 5 and J 6 Same or different, and each is independently selected from the key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently optionally composed of one or more R groups. 6 Replaced; L 1 L 2 L 3 L 4 L 5 and L 6 They may be the same or different, and each is independently selected from the bond, O, and S(O). v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L ), alkenyl, alkyneyl, cycloalkyl, heterocyclic, (CR) e R f ) u -Heterocyclic group, heterocyclic group-(CR) e R f ) u 、(CR e R f ) u -heterocyclic-(CR) e R f ) u aryl and heteroaryl; each of the alkenyl, alkyneyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally composed of one or more R 7 Replaced; Each R a R b R c R d R e and R f The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected by one or more R 03 Replaced; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is optionally independently bound by one or more R... 03 Replaced; R 4 R m R 11 R 12 R 13 R 14 R J and R L The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced; Each R 6 R 7 R 8 R 01 R 02 and R 03 The same or different, and each independently selected from deuterium, oxo group, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 21 R 22 C(O)NR 21 R 22 alkylene NR 21 R 22 alkylene C(O)NR 21 R 22 NR 23 C(O)R 24 C(O)R 24 C(O)OR 24 S(O) v R 24 S(O) v OR 24 OR 24 S(O) v NR 21 R 22 =CR 15 R 16 =NR 23 , cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl; R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, and heterocyclic groups; Each R 21 R 22 R 23 and R 24 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups; x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6; u can be 0, 1, 2, 3, 4, 5, or 6; a can be 0, 1, 2, 3, 4, 5, or 6; t can be 0, 1, 2, 3, 4, 5, or 6. r is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and v can be 0, 1, or 2.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: J 4 It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; preferably, J 4 It is selected from cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl and tetrahydrofuranyl; more preferably selected from cyclopropyl, cyclobutyl and cyclopentyl.

3. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a pharmaceutically acceptable salt thereof is: in, Ring B is a cycloalkyl or heterocyclic group; B 1 B 2 and B 3 Whether they are the same or different, and each is independently N or CR 7a ;R 7a For hydrogen atoms or R 7 ; R 1 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, deuterated alkyl groups, deuterated alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups; s is 0, 1, 2, or 3; t is 0, 1, 2, or 3; s1 is 0 or 1; b1 and b2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently; m, p, q, y1 and y2 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6; y3 and y4 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6; Rings A, V, L 3 L 5 、u、J 1 R 2 To R 8 and r as defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from Preferably, ring A is selected from z is 0, 1, 2, or 3; X, Y, t1, t2, a1, a2, A 1 A 2 and R X As defined in claim 1; more preferably, ring A is selected from... The aforementioned ring can be arbitrarily selected by R. 8 Replace, R 8 As defined above; more preferably, ring A is selected from...

5. The compound of general formula (I) according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (IIIN), (IVN) or (VN), or a pharmaceutically acceptable salt thereof: in, E 1 Selected from keys, (CR g R h ) y3 、(CR g R h ) y5 O(CR g R h ) y6 和(CR g R h ) y5 NR m (CR g R h ) y6 ; E 2 Selected from (CR g R h ) y4 、(CR g R h ) y7 O(CR g R h ) y8 and (CR g R h ) y7 NR m (CR g R h ) y8 ; R g For hydrogen atoms or R 6 ;R h For hydrogen atoms or R 6 m can be 0, 1, or 2; y5 and y6 are each independently 0, 1 or 2; y7 and y8 are each independently 0, 1 or 2. W, V, X 1 X 2 X 3 ,X,Y,t1,t2,a1,a2,A 1 A 2 R 8 ,r,L 5 B 1 B 2 B 3 Ring B, b1, b2, s1, u, J 1 y1 to y4, R m R 1 To R 7 p, q, s, and t are as defined in claim 3.

6. The compound of general formula (I) according to claim 1, 4 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (VI), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof: in, E 1 E 2 R 1 R 2 R 3 , u, ring B, B 3 R 7 , q, L 5 A 2 R 8 r, t1, t2, X 3 and R X As defined in claim 5.

7. The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein, Y is a bond or O, and / or X is selected from a bond, O and CH2, and / or A. 1 For CH or N, and / or A 2 Selected from CH, N, CF and C-OH, and / or a1 is 0 or 1, and / or a2 is 0 or 1, and / or t1 is 0 or 1, and / or t2 is 0 or 1; preferably, Y is O, and / or X is a bond or O, and / or A 1 For CH or N, and / or A 2 Y is CH or N, and / or a1 is 0 or 1, and / or a2 is 0 or 1, and / or t1 is 0 or 1, and / or t2 is 0 or 1; more preferably, Y is O, and / or A 1 For N, and / or A 2 It is CH or N, and / or a1 is 1, and / or a2 is 1, and / or t1 is 0, and / or t2 is 1.

8. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein, B 1 For CH or N, and / or B 2 For CH or N, and / or B 3 It is CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1, and / or ring B is a 3 to 10-membered cycloalkyl or a 3 to 10-membered heterocyclic group; preferably, ring B is a 5 or 6-membered cycloalkyl or a 5 or 6-membered heterocyclic group.

9. The compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, s1 is 1, and / or u is 0 or 1, and / or L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; preferably, u is 0, and / or L. 5 For key.

10. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein, J 1 For a bond or 0, and / or y1 is 0, 1, 2 or 3, and / or y2 is 0, 1 or 2, and / or y3 is 0, 1 or 2, and / or y4 is 1 or 2; preferably, J 1 For y1, y2 is 0, y3 is 0, y4 is 1 or 2; more preferably, J is 0, y5 is 0, y6 is 1 or 2. 1 If y1 is 0, and / or y2 is 1, and / or y3 is 1, and / or y4 is 1 or 2.

11. The compound of formula (I) according to any one of claims 3 to 9, or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl and C 3-6 Heterocyclic groups, and / or R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups, and / or R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups, and / or R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl, and / or R 5 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups, and / or each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; preferably, R 1 C 1-6 Alkyl, and / or R 2 For hydrogen atoms, and / or R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms, and / or R 5 For hydrogen atoms, and / or each R X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; more preferably, R X It can be a hydrogen atom or a halogen.

12. The compound of general formula (I) according to any one of claims 5 to 11, or a pharmaceutically acceptable salt thereof, wherein E 1 Selected from (CH2) y3 (CH2) y5 O, O(CH2) y6 (CH2) y5 NR m and NR m (CH2) y6 ; and / or E 2 Selected from (CH2) y4 (CH2) y7 O, O(CH2) y8 (CH2) y7 NR m and NR m (CH2) y8 Preferably, E 1 Selected from CH2, O and NR m , and / or E 2 Selected from CH2, CH2CH2, CH2O, OCH2, CH2NR m and NR m CH2; R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, E 1 For CH2 or O, and / or E 2 It is CH2CH2.

13. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

14. A compound of general formula (IIINA-1) or a salt thereof: in, R W The protecting group can be a hydrogen atom or an amino group; the amino protecting group is preferably Boc. Ring B, B 1 B 2 ,u,b1,b2,s1,p,q,J 1 E 1 E 2 R 1 To R 7 , s, t, y1, y2 and m are as defined in claim 5.

15. A compound of the general formula (IIIB), (IV-1B), (VB), (V-3B), (V-4B), or a salt thereof: in, R W The protecting group can be a hydrogen atom or an amino group; the amino protecting group is preferably Boc. X, Y, V, t1, t2, a1, a2, L 6 A 1 R X And z as defined in claim 5.

16. A compound or a salt thereof, selected from the following structures:

17. A method for preparing a compound of general formula (VN) or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IIINA) or its salt reacts with the compound of general formula (VMB-3) or its salt (preferably trifluoroacetate or hydrochloride) in a reductive amination reaction to give B. 3 For CH, L 5 As key and A 2 Compounds of the general formula (VN) for N or their pharmaceutically acceptable salts, or The compound of general formula (IIINA-2) or its salt (preferably trifluoroacetate or hydrochloride) undergoes a reductive amination reaction with the compound of general formula (VMB-2) or its salt to give B. 3 For N, L 5 As key and A 2 Compounds of the general formula (VN) CH or their pharmaceutically acceptable salts. in, W, V, X 1 X 2 X 3 Y, t1, t2, a1, a2, A 1 R 8 ,r,B 1 B 2 Ring B, b1, b2, s1, u, J 1 E 1 E 2 y1, y2, m, R 1 To R 7 p, q, s, t are as defined in claim 5.

18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for regulating EGFR ubiquitination and degradation.

20. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for the treatment and / or prevention of EGFR-mediated or dependent diseases or conditions.

21. Use of the compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating and / or preventing cancer; preferably, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; more preferably lung cancer; more preferably non-small cell lung cancer.

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